Proteomimetic compounds and methods

ABSTRACT

The present invention relates to compounds and pharmaceutical compositions which are proteomimetic and to methods for inhibiting the interaction of an alpha-helical protein with another protein or binding site. Methods for treating diseases or conditions which are modulated through interactions between alpha helical proteins and their binding sites are other aspects of the invention.

RELATED APPLICATIONS

[0001] This application claims the priority benefit of provisionalapplication No. 60/289,640, entitled “Structure and functional mimics ofa helix”, filed May 8, 2001.

FIELD OF THE INVENTION

[0002] The present invention relates to compounds and pharmaceuticalcompositions which are proteomimetic and to methods for inhibiting theinteraction of an alpha-helical protein with another protein or bindingsite. Methods for treating diseases or conditions which are modulatedthrough interactions between alpha helical proteins and their bindingsites are other aspects of the invention. Methods of inhibiting thebinding of proteins to their binding sites are other aspects of thepresent invention.

BACKGROUND OF THE INVENTION

[0003] The design of synthetic structures that mimic large andnon-contiguous regions of a protein surface remains an extremelyimportant but elusive goal.¹ There has been considerable success in thefield of small peptidomimetics that reproduce features of short peptidesin extended² or β-turn conformations.³ However, much less progress hasbeen made in the search for proteomimetics or non-peptide structuresthat mimic larger areas of the protein surface⁴ such as an α-helix.⁵This is remarkable given the ubiquitous role of α-helical regions inmediating protein-protein interactions.⁶ The difficulty clearly lies inthe large and elongated surface area that is presented by 2-4 turns ofan α-helix. One strategy involves the covalent or non-covalentstabilization of a 16-20-mer peptide in a helical conformation eitherthrough side chain contacts,⁷ end capping templation,⁸ specific folding⁹or use of β-peptides.¹⁰ However, these approaches suffer the normallimitations of flexibility and instability associated with using peptidederivatives. As part of our interest in helix surfacerecognition,^(11,12) the inventors of the present application sought anentirely non-peptidic scaffold that could be synthesized in a modularfashion and project side chain functionality with similar distance andangular relationships to those found in α-helices. One aspect of thepresent application, therefore, relates to a new family ofproteotmimetics, based on a functionalized terphenyl and relatedstructure scaffold, that are structural mimics of two turns of themyosin light chain kinase α-helix and show functional analogy in bindingwith high affinity to calmodulin.

[0004] In α-helix-protein complexes critical interactions are oftenfound along one face of the helix, involving side chains from the i,i+3, and i+7 residues.⁶ The relative positions of these groups in anall-Ala α-helix have been shown and compared to the projection ofsubstituents in a tris-functionalized 3,2′,2″-terphenyl derivative.¹³This is an attractive template for proteomimetic design due to thesimplicity of the structure and the potential for an iterativesynthesis. The alternating arrangement of i, i+3, and i+7 groups throughtwo turns in the helix compares well with the 3,2′,2″-substituents whenthe terphenyl is in a staggered conformation with dihedral angles of 68°and 36° between the phenyl rings.¹⁴ In this easily accessibleconformation, the three subsituents project from the terphenyl core withsimilar angular relationships and 4-25% shorter distances than betweenthe i, i+3, and i+7 β-carbons in an α-helix.¹⁵

OBJECTS OF THE INVENTION

[0005] It is an object of the invention of the present invention toprovide novel compounds which exhibit proteomimetic characteristics, andin particular, mimic α-helical proteins.

[0006] It is another object of the invention to provide pharmaceuticalcompositions based upon the compounds according to the present inventionwhich are useful to treat disease states or conditions which aremodulated through the interaction of an α-helix protein with anotherprotein or binding site for the protein.

[0007] It is still another object of the invention to provide methodsfor treating disease states or conditions which are modulated throughthe interaction of an α-helical protein with another protein or bindingsite for the protein.

[0008] It is yet another object of the present invention to provide amethod of providing compounds which exhibit proteomimeticcharacteristics.

[0009] These and/or other objects of the present invention may bereadily gleaned from the description of the invention which follows.

DESCRIPTION OF THE FIGURES

[0010]FIG. 1 shows a general chemical synthetic scheme for producingterphenyl compounds according to the present invention.

[0011]FIG. 2 is a scheme representing the chemical synthesis ofsubstituted phenyl derivative 6. The following legend applies to FIG. 2,Scheme 2: a) (i) isopropyl triphenylphosphonium iodide, BuLi, Et₂O, 0°C.-rt, 35 min, (ii) 9, rt, 20 h, 61%; b) H₂ (60 psi), 10% Pd/C, EtOH,rt, 9 h, 84%; c) Selectfluor reagent, I₂, CH₃CN, rt, 8 h, 73%; d)bis(pinacolato)diboron, KOAc, PdCl₂dppf, DMSO, 85° C., 3 h, 67%; e)dioxane dibromide, Et₂O, 0° C.-rt, 30 min, 66%; f) MeI, K₂CO₃, acetone,56° C., 24 h, 91%; g) (i) BuLi, THF, −78° C., 30 min, (ii) B(OMe)₃, rt,24 h, (iii) NaOH, rt, 1 h, (iv) HCl, 95%; h) acrylonitrile, Pd(OAc)₂,tetra-n-butylammonium chloride, NaHCO₃, DMF, 40° C., 19 h, 74%; i) (i)Mg, MeOH, 0° C.-rt, 5 h, (ii) 6M HCl, 96%; j) BBr₃, CH₂Cl₂, 10° C., 9 h,99%; k) Tf₂O, pyridine, 0° C.-rt, 17 h, 93%.

[0012]FIG. 3 is a scheme representing the chemical synthesis ofterphenyl derivative 3 and biphenyl derivative 4. The following legendapplies to FIG. 3, Scheme 3: a) H₂ (20 psi), 10% Pd/C, EtOH, rt, 12 h,91%; b) Tf₂O, pyridine, 0° C.-rt, 48 h, 92%; c) 1,4-phenylenebisboronicacid, Pd(PPh₃)₄, Na₂CO₃ (aq), DME/EtOH, 80° C., 36 h, 79%; d) (i) NaOH,dioxane/H₂O/HMPA, 110° C., 2 h, (ii) HCl, 95%; e) ClCH₂CN, K₂CO₃,acetone, 45° C., 24 h, 66%; f) bis(pinacolato)diboron, KOAc, PdCl₂dppf,DMSO, 85° C., 16 h, 80%; g) (i) 4-bromophenylhydrocinnamonitrile,Pd(PPh₃)₄, Na₂CO₃ (aq), DME, 80° C., 24 h, (ii) NaOH, MeOH/H₂O, 50° C.,24 h, (iii) HCl, 93%.

[0013]FIG. 4, is a scheme representing the chemical synthesis ofterphenyl derivatives as depicted. The following legend applies to FIG.4, Scheme 4: a) Br₂, CH₂Cl₂/H₂O, rt, 19 h, 92%; b) (i) SOCl₂, toluene,DMF, 70° C., 1.5 h, (ii) AlCl₃, benzene, rfl., 5 h, 90%; c) NaBH₄, MeOH,rt, 2 h, 98%; d) (i) LiAlH₄, AlCl₃, Et₂O, rfl., 12 h, 62%; e) MeI,K₂CO₃, acetone, rfl., 24 h, 98%; f) (i) n-BuLi, THF, −78° C., 30 min,(ii) B(OMe)₃, rt, 24 h, (iii) H₂O, 10% aq. NaOH, rt, 1 h; g)bis(pinacolato)diboron, KOAc, PdCl₂dppf*CH₂Cl₂, DMSO, 85° C., 3 h, 55%;h) Pd(Ph₃P)₄, DME/EtOH (9+1), 2 M aq. Na₂CO₃, 80° C., 17 h, 52%; i)BBr₃, CH₂Cl₂, 0° C.-rt, 9 h, 96%; j) Tf₂O, Py, 0° C.-rt, 18 h, 85%; k)23, Pd(Ph₃P)₄, DME/EtOH (9+1), 2 M aq. Na₂CO₃, 80° C., 8 h, 91%; l)BBr₃, CH₂Cl₂, 0° C.-rt, 6 h, 86%; m) K₂CO₃, acetone, ClCH₂CN, 55° C., 40h, 97%; n) 25% aq. NaOH, MeOH/THF (1:1), rfl., 24 h, 11%.

[0014]FIG. 5A represents the chemical synthesis of alternative Terphenylderivatives according to the present invention which areCaM-binding-peptide mimetic. The following legend applies to FIG. 5A,Scheme 5A: (a) PhMgBr, THF; (b) H₂, Pd/C, MeOH; (c) NaNO₂, HCl, EtOH;(d) H₂, Pd/C, HCl, THF; (e) NaNO₂, H₂SO₄, KI, Cu; (f) tBDMSCl, imid.,DMF; (g) tBuLi, ZnCl₂, THF; (h)Tf₂O, TEA, DCM; (i) A, Pd₂dba₃, dppf,THF; (j) TBAF; (k) B, Pd₂dba₃, dppf, THF; (l) BrCH₂CO₂Bn, K₂CO₃, DMF;(m) KOH, MeOH/DCM; (n) NH₄OH.

[0015]FIG. 5B represents the chemical synthesis of alternative Terphenylderivatives according to the present invention which represent secondgeneration CaM-binding-peptide mimetic. The following legend applies toFIG. 5A, Scheme 5A: (a) BnBr, K₂CO₃; (b) 2-Li-napthalene or1-Li-napthalene, THF; (c) H₂, Pd/C, THF; (d)Tf₂O, TEA, DCM; (e) A,Pd₂dba₃, dppf, THF; (f) TBAF; (g) B, Pd₂dba₃, dppf, THF; (h) BrCH₂CO₂Bn,K₂CO₃, DMF; (i) KOH, MeOH/DCM; (j) NH₄OH.

[0016]FIG. 6 represents the chemical synthesis of the terphenylderivatives as indicated. The following legend applies to FIG. 6: a:Pd(Ph₃P)₄, DME/EtOH (9+1), 2 M aq. Na₂CO₃, 80° C., 17 h, 52%. b: BBr₃,CH₂Cl₂, 0° C.-r.t., 9 h, 96%. c: Tf₂O, Py, 0° C.-r.t., 18 h, 85%. d:Pd(Ph₃P)₄, DME/EtOH (9+1), 2 M aq. Na₂CO₃, 80° C., 19 h, 88%. e: BBr₃,CH₂Cl₂, 0° C.-r.t., 6.5 h, 100%. f: K₂CO₃, acetone, ClCH₂CN, 55° C., 40h, 91%. g: 25% aq. NaOH, MeOH/THF (1:1), rfl., 24 h, 77%.

[0017]FIG. 7 represents the chemical synthesis of the terphenylderivatives as indicated. The following legend applies to FIG. 7: a:n-BuLi, THF, −78° C. (1.5 h), −30° C. (2 h), r.t. (3.5 h), 88%. b:NaBH₄, TFA, CH₂Cl₂, r.t., 24 h, 96%. c: bis(pinacolato)diboron, KOAc,PdCl₂dppf*CH₂Cl₂, DMSO, 85° C., 5 h, 67%. d: Pd(Ph₃P)₄, DME/EtOH (9+1),2 M aq. Na₂CO₃, 80° C., 15 h, 88%. e: BBr₃, CH₂Cl₂, 0° C. (2 h), r.t.(14 h), 94%. f: Tf₂O, Py, 0° C. (1 h), r.t., 19 h, 90%. g: 12,Pd(Ph₃P)₄, DME/EtOH (9+1), 2 M aq. Na₂CO₃, 80° C., 9 h, 94%. h: BBr₃,CH₂Cl₂, 0° C. (1 h), r.t. (12 h), 99%. i: K₂CO₃, acetone, ClCH₂CN, 55°C., 24 h, 98%. J: HCl(g), MeOH, rfl., 1.5 h, 88%. k: 25% aq. NaOH, 40%aq. Bu₄NOH, 1,4-dioxane, rfl., 24 h, 100%.

[0018]FIG. 8 represents the chemical synthesis of the terphenylderivatives as indicated. The following legend applies to FIG. 8: a:Pd(Ph₃P)₄, DME/EtOH (9+1), 2 M aq. Na₂CO₃, 80° C., 17 h, 99%. b: BBr₃,CH₂Cl₂, 0° C. (3 h), r.t. (10 h), 9 h, 66%. c: Tf₂O, Py, 0° C. (3 h),r.t. (14 h), 84%. d: 20, Pd(Ph₃P)₄, DME/EtOH (9+1), 2 M aq. Na₂CO₃, 80°C., 22 h, 80%. e: BBr₃, CH₂Cl₂, 0° C. (3 h), r.t. (12 h), 63%. f: K₂CO₃,acetone, ClCH₂CN, 55° C., 40 h, 78%. g: HCl(g), MeOH, rfl., 1 h, 87%. h:25% aq. NaOH, 40% aq. Bu₄NOH, 1,4-dioxane, rfl., 24 h, 100%.

[0019]FIG. 9 represents the chemical synthesis of the piperazinederivatives as indicated. The following legend applies to FIG. 9: a: (i)4-methylmorpholine, EtOAc, −15° C.; (ii) ethyl chloroformate, 15 min,−15° C; (iii) 4-methylmorpholine, 1 h (−15° C.), 12 h (r.t.), (93%). b:(i) Pd/C, H₂, MeOH, r.t., 4 h; (ii) MeOH, rfl., 24 h, (100%). c: (i)COCl₂ (20% soln. in toluene), THF, 55° C., 4 h, (47%). d: (i) NEt₃,CHCl₃, −78° C. (3 h), −20° C. (12 h). e: (i) toluene, rfl., 24 h, (21%).f: (i) 1.) BH₃*THF, THF, rfl., 30 h; 2.) 30% HBr in HOAc; 3.) NH₄OH,(94%). g: Boc₂O, t-BuOH, H₂O, 2.5 N aq. NaOH, 0° C. (1 h), r.t. (24 h),(98%).

[0020]FIG. 10 represents the chemical synthesis of the piperazinederivatives as indicated. The following legend applies to FIG. 10: a:Pd₂(dba)₃, P(o-tolyl)₃, toluene, NaOt-Bu, 100° C., 19 h, (19%); (23%).b: Pd₂(dba)₃, P(o-tolyl)₃, toluene, NaOt-Bu, 100° C., 19 h, (11%).

[0021]FIG. 11 represents a synthetic route to alternative terphenylderivatives of the present invention. The following legend applies toFIG. 11: a) Pd(PPh₃)₄, Na₂CO₃ (aq), DME/EtOH, 80° C., 17 h, 98%; b)BBr₃, CH₂Cl₂, 0-10° C., 9 h, 92%; c) Tf₂O, pyridine, 0° C.-rt, 17 h,95%; d) Pd(PPh₃)₄,2-(3-isobutyl-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,Na₂CO₃ (aq), DME/EtOH, 80° C., 20 h, 87%; e) BBr₃, CH₂Cl₂, 0-10° C., 9h, 97%; f) CH₂ClCN, K₂CO₃, acetone, 55° C., 40 h, 95%; g) NaOH (aq),MeOH, 50° C., 24 h, 74%.

[0022]FIG. 12 represents shows the design of a number of compoundsaccording to the present invention using as a template the RS20 20 merpeptide of smMLCK. Four proteomimetic compounds according to the presentinvention are set forth in FIG. 12.

[0023]FIG. 13 shows the results of an experiment wherein the antagonismof CaM was monitored by phosphodiesterase hydrolysis of mant-cGMP forthe compounds which are set forth in FIG. 12. The following legendapplies to FIG. 13 ♦=d, ▪=a, =RS-20, ▾=b Δ=c. 13.9 nM CaM, 50 mu/mlPDE, 8 μM mant-cGMP, 10 mM Mops, 0.5 mM MgCl₂, 90 mM KCl, 0.73 mM CaCl₂,0.2% DMSO, pH 7.0.

[0024]FIG. 14 shows a number of exemplary inhibitors of gp-41 disruption(HIV).

[0025]FIG. 15 shows the CD spectra of a 10 μM solution (50 mM PBS, 150mM NaCl, pH 7.0, 4° C.) of the gp41 core model upon titration of f (0-50μM). The arrow indicates the reduction in signal at θ222 and 208 nm.

[0026]FIG. 16 shows the CD signal at θ222 nm versus inhibitorconcentration: f (▪); g (♦); h (); i (+); j (▴). The inhibitors weretitrated into a 10 μM aqueous solution of the gp41 model complex (50 mMPBS, 150 mM NaCl, pH 7.0, 4° C.).

[0027]FIG. 17 shows a number of proteomimetic compounds for Bcl-x_(L).

[0028]FIG. 18 shows the results of an assay system using the compoundspresented in FIG. 17. The figure exhibits the results of fluorescencepolarization experiments measuring the displacement of fluoresceinlabelled Bak peptide from BcLxL.

[0029]FIG. 19, Scheme 19, represents a synthetic route to alternativeterpyridyl derivatives of the present invention.

DESCRIPTION OF THE INVENTION

[0030] The present invention relates to compounds according to thegeneral formula:

W—B—X—B—Y

[0031] Where X is selected from the group consisting of a five orsix-membered ring selected from the group consisting of

[0032]  or a fused-ring system according to the structure:

[0033] W and Y are each independently selected from the group consistingof

[0034] Where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from the group consisting of unsubstituted orsubstituted hydrocarbon, preferably an alkyl or alkylene group,unsubstituted or substituted aryl, including benzyl and naphthyl,alkylenearyl, alkylaryl, (preferably alkylene phenyl and alkylphenyl,)alkoxy, ester (including an alkyl or aryl ester or an alkylene esterwherein said ester group preferably comprises a C₁-C₆ alkyl or aryl,preferably benzyl or phenyl group), alkanol, alkanoic acid (said termincluding embracing a carboxylic acid without further substitution),thioester (preferably a C₁-C₆ alkyl/C₁-C₆ alkylene thioester), thioether(preferably a C₁-C₆ alkyl/C₁-C₆ alkylene thioether, even more preferablya methyl ethylene as methionine thioether), substituted or unsubstitutedamine (including an alkylamine and dialkylamine, preferably C₁-C₆alkyl), substituted or unsubstituted alkylamide (preferably, C₁-C₆alkyl), substituted or unsubstituted alkylene amide (preferably C₁-C₆alkylene which may be substituted on the amine groups of the amide,preferably with alkyl groups), substituted or unsubstitutedalkyleneamine (preferably C₁-C₆ alkylene, such term including saturatedring systems containing nitrogen groups), alkyleneguanidine (preferablyC₁-C₆ alkylene); preferably a C₁-C₆ alkanol, C₁-C₆ alkanoic acid, orC₁-C₆ alkylamide, C₁-C₆ alkyleneamine or a C₁-C₆ alkyleneguanidine;

[0035] R_(n) is a C₁-C₁₀ (preferably, C₁-C₆) alkyl, alkanol or aryl, ora

[0036]  group, where T is H or a C₁-C₁₂ saturated or unsaturatedhydrocarbon (forming an amide with the ring nitrogen) group, amine,alkylamine, dialkylamine (all preferably C₁-C₆ alkyl), substituted orunsubstituted alkyleneamine (preferably, C₁-C₆) or substituted orunsubstituted alkyleneamide (preferably, C₁-C₆);

[0037] Z is O or S; and

[0038] B is a single bond between carbon atoms of W—X or X—Y groups oran ester or amide group linking W—X or X—Y groups.

[0039] In certain preferred aspects of the present invention X is aphenyl, piperazinyl or pyridinyl group as set forth above and W and Yare selected from the group consisting of phenyl, piperazinyl,pyridinyl, napththyl and indole, preferably W and Y are phenyl,piperazinyl or pyridinyl and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ areeach independently selected from the group consisting of H, C₁-C₆ alkyl,benzyl, 4-hydroxybenzyl, C₁-C₆ alkanol, C₁-C₆ alkanoic acid, C₁-C₆alkylamide, C₁-C₆ alkyleneamine, C₁-C₆ alkyleneguanidine with theproviso that no more than two R substituents on each of W, X or Y groupsare other than H;

[0040] R_(n) is a C₁-C₁₀ alkyl, alkanol, aryl or a

[0041]  group, where T is H or a C₁-C₆ alkyl, amine, C₁-C₆ alkylamine,C₁-C₆ dialkylamine, unsubstituted or substituted C₁-C₆ alkyleneamine orunsubstituted or substituted C₁-C₆ alkyleneamide;

[0042] Z is O or S; and

[0043] B is a single bond between carbon atoms of W—X or X—Y groups oran amide group linking W—X or X—Y groups.

[0044] Compounds according to the present invention may be used asactive agents in pharmaceutical compositions as agonists or inhibitorsof α-helical proteins in their interactions with proteins (such asreceptors, enzymes, other proteins) or other binding sites, saidcompositions comprising an effective amount of one or more of thecompounds disclosed above, formulated as a pharmaceutical dosage form,optionally in combination with a pharmaceutically acceptable carrier,additive or excipient. Pharmaceutical compositions according to thepresent invention may be used in the treatment of cancer (as, forexample, a suppressor of Mdm2/p53 tumor, to inhibit BcL proteinfamily/Bak protein family or AP-1 transcription factor/DNA complex),proliferative diseases including, for example, psoriasis, genital wartsand hyperproliferative keratinocyte diseases including hyperkeratosis,ichthyosis, keratoderma or lichen planus, neuropeptide Y receptorinteractions, including the resulting hypertension and andneuronal/neurological effects (to facilitate neuromodulation through,for example, inhibition of calmodulin binding on calmodulin dependentphosphodiesterase including PDE1A, PDE1B and PDE1C, among others),neurodegenerative diseases including Alzheimer's disease and Parkinson'sdisease, Herpes simplex virus infections (HSV, through inhibition of theHSV VP16/human TAF1131 HSV infection complex), HIV infections (throughinhibition of HIVp7 nuclear capsid protein/RNA interaction oralternatively, through inhibition of the REV protein RNA complex),asthma, hypertension, cancer and autoimmune diseases (throughimmunomodulation, for example, by inhibition or modulation ofinterleukin/receptor interaction), numerous viral infections other thanHIV or HSV through inhibition of ribonucleotide reductase dimerization,or to modulate nuclear receptor/coactivator protein complex interaction(eg. estrogen receptor for anticancer therapy) and to disrupt G proteincoupled receptor (GPCR) function (through displacement of one of thehelixes and disruption of the helix packing interactions oralternatively, by blocking the interacton of the ligand with GPCR, e.g.where the ligand contains a key helix binding domain (e.g. GCSF,calcitonin, interleukins, parathyroid hormones, among others).

[0045] In other aspects of the present invention, certain compoundsaccording to the present invention may be used as agonists orantagonists in binding assays, as analytical agents, as agents to beused to isolate or purify proteins, and as intermediates in thesynthesis of further peptidomimetic agents, among other uses.

[0046] The present invention also relates to methods of treatingpatients in need thereof for conditions or disease states which aremodulated through interactions between alpha helical proteins and otherproteins or binding sites are other aspects of the invention. Thus, inthe method aspect of the present invention, pharmaceutical compositionscomprising α-helical protein agonists or antagonists may be used totreat any condition or disease state in which α-helical proteinsmodulate their activity through a receptor or other binding site. Inparticular, the method aspect of the present invention relates to theinhibition of protein binding to binding sites within the patient inorder to effect a biological/pharmacological result. Compounds accordingto the present invention may be used as proteomimetics to inhibit theinteraction between a native α helical protein (i.e., a natural αhelical protein normally found in a patient) and its binding site.Preferred compounds according to the present invention may be used todisrupt or compete with the binding of a number of proteins including,for example, calmodulin (CaM) with binding sites on smooth muscle lightchain kinase (smMLCK) or phosphodiesterase (PDE1A, PDE1B, PDE1C) withresulting neuromuscular and neuronal (among other) effects in thetreating of disease states or conditions, gp41 (HIV) and other virusessuch as HSV or HBV, for the viral invasive binding cites in CD4 and/orother hematopoietic cells, genital/mucosal cells, among others (HSV) andhepatocytes (HBV), among numerous others and pro-apoptotic Bak- and/orBad-proteins, for their binding interaction with Bcl-x_(L) protein in apreferred treatment for cancer.

[0047] Thus, the present application is directed to the treatment ofdisease states or conditions which are modulated through interactionsbetween α-helical proteins and other proteins or binding sites of theα-helical proteins selected from the group consisting of viralinfections (including Hepatitis B virus (HBV) infections, humanimmunodeficiency virus (HIV) infections or conditions associated withsuch infections (AIDS), Herpes Simplex virus infections (HSV)infections, tumors and/or cancer, proliferative diseases includingpsoriasis, genital warts and hyperproliferative keratinocyte diseasesincluding hyperkeratosis, ichthyosis, keratoderma, lichen planus,hypertension, neuronal disorders by promoting neuromodulation including,for example, attention deficit disorder, memory loss, language andlearning disorders, asthma, autoimmune diseases including lupus (lupuserythematosus), multiple sclerosis, arthritis, including rheumatoidarthritis, rheumatic diseases, fibromyalgia, Sjögren's disease andGrave's disease and neurodegenerative diseases including Alzheimer'sdisease and Parkinson's disease, said method comprising administering toa patient in need thereof an effective amount of a pharmaceuticalcomposition comprising any one or more of the compounds previouslydescribed above.

[0048] Definitions

[0049] The following definitions shall be used when describing thepresent invention.

[0050] “Patient” refers to a mammal, preferably a human, in need oftreatment or therapy to which compounds according to the presentinvention are administered in order to treat a condition or diseasestate modulated through the binding of an α-helical protein with abinding site.

[0051] “Modulated” means, with respect to disease states or conditionsmodulated through binding of α-helical proteins to binding sites, thatthe binding or lack or absence of binding of an α-helical protein to abinding site produces or will produce, either directly or indirectly, acondition or disease state which is sub-optimal and in many cases,debilitating and even life threatening.

[0052] “Sterically and electronically similar” refers to syntheticsubstituents on chemical cages or scaffolds according to the presentinvention which mimic the steric and/or electronic physicochemicalcharacteristics of substituents on α carbons in natural α helicalproteins. While not necessarily identical to the natural substituents,substituents which are sterically and electronically similar to thenatural substituents promote the binding of synthetic compoundsaccording to the present invention to α helical protein binding sites.

[0053] “Chemical cages or scaffords” according to the present inventionrepresent terphenyl or other structures as otherwise disclosed herein inwhich three cyclical chemical moieties are bound together directlythrough chemical bonds or through amide or ester groups) and aresubstituted with groups bound to one or more of the three cyclicalchemical moieties. These chemical cages are generally substituted withany number of substituents, preferably those which mimic naturalsubstituents on α carbons (from the amino acids) of α helical proteins.

[0054] “Hydrocarbon” refers to any monovalent radical containing carbonand hydrogen, which may be straight or branch-chained or cyclic innature. Hydrocarbons include linear, branched and cyclic hydrocarbons,including alkyl groups, alkylene groups, unsaturated hydrocarbon groups,both substituted and unsubstituted.

[0055] “Alkyl” refers to a fully saturated monovalent radical containingcarbon and hydrogen, and which may be cyclic, branched or a straightchain. Examples of alkyl groups are methyl, ethyl, n-butyl, n-hexyl,isopropyl, 2-methylpropyl, cyclopropyl, cyclopropyl-methyl, cyclobutyl,cyclopentyl, cyclopentylethyl, and cyclohexyl. “Alkylene” refers to afully saturated hydrocarbon which is divalent (may be linear, branchedor cyclic). Other terms used to indicate substitutuent groups incompounds according to the present invention are as conventionally usedin the art. Thus, the term alkylene phenyl includes a benzyl group orethylene phenyl group, alkylphenyl includes a phenyl group which hasalkyl groups as substituents, etc.

[0056] “Aryl” refers to a substituted or unsubstituted monovalentaromatic radical having a single ring (e.g., benzene) or multiplecondensed rings (e.g., naphthyl, anthracenyl, phenanthryl). Otherexamples of aryl groups include heterocyclic aromatic ring systemshaving one or more nitrogen, oxygen, or sulfur atoms in the ring, suchas imidazole, furyl, pyrrole, pyridyl, indole and fused ring systems,among others, which may be substituted or unsubstituted.

[0057] The term “effective amount” refers to the amount of a selectedcompound which is effective within the context of its use oradministration. In the case of therapeutic methods according to thepresent invention, the precise amount required will vary depending uponthe particular compound selected, the age and weight of the subject,route of administration, and so forth, but may be easily determined byroutine experimentation.

[0058] The term “substituted” shall mean substituted at a carbon (ornitrogen) position with an alkyl group (preferably, C₁-C₆), alkoxy group(preferably, C₁-C₆ alkyl or aryl), ester (preferably, C₁-C₆ alkyl oraryl) including alkylene ester (such that attachment is on the alkylenegroup, rather than at the ester function which is preferably substitutedwith a C₁-C₆ alkyl or aryl group), thioether (preferably, C₁-C₆ alkyl oraryl), thioester (preferably, C₁-C₆ alkyl or aryl), (preferably, C₁-C₆alkyl or aryl), halogen (F, Cl, Br, I), nitro or amine (including afive- or six-membered cyclic alkylene amine, preferably, a C₁-C₆ alkylamine or C₁-C₆ dialkyl amine), alkanol (preferably, C₁-C₆ alkyl oraryl), or alkanoic acid (preferably, C₁-C₆ alkyl or aryl). Preferably,the term “substituted” shall mean within its context alkyl, alkoxy,halogen, nitro and amine (including mono- or di-alkyl substitutedamines). The term unsubstituted shall mean substituted with one or moreH atoms.

[0059] The term “binding site” refers to a site at which an α-helicalprotein binds and elicits some response or action at that binding site,which action may be direct or indirect. Compounds according to thepresent invention will also bind at the binding site of the α-helicalbinding site in an agonistic or antagonistic manner. The binding sitemay be another protein, a receptor (such as a cell surface receptor or aG-protein coupled receptor), signaling proteins, proteins involved inapoptotic pathways (especially neuronal apoptosis), active sites andregulatory domains of enzymes, growth factors, DNA, RNA (includingpolynucleotides and oligonucleotides), viral fusion proteins and viralcoat proteins, among numerous others.

[0060] The term “pharmaceutically acceptable carrier” refers to carrier,additive or excipient which is not unacceptably toxic to the subject towhich it is administered. Pharmaceutically acceptable excipients aredescribed at length by E. W. Martin, in “Remington's PharmaceuticalSciences”, among others well-known in the art.

[0061] A “pharmaceutically acceptable salt” of the present compoundgenerally refers to pharmaceutically acceptable salts of an aminecompound, such as those contemplated in the current invention, such asan ammonium salt having as counterion an inorganic anion such aschloride, bromide, iodide, sulfate, sulfite, nitrate, nitrite,phosphate, and the like, or an organic anion such as acetate, malonate,pyruvate, propionate, fumarate, cinnamate, tosylate, and the like.Certain compounds according to the present invention which havecarboxylic acid groups may also form pharmaceutically acceptable salts,generally, as carboxylate salts.

[0062] Aspects of the present invention include compounds which havebeen described in detail hereinabove or to pharmaceutical compositionswhich comprise an effective amount of one or more compounds according tothe present invention, optionally in combination with a pharmaceuticallyacceptable carrier, additive or excipient.

[0063] Another aspect of the present invention is directed to compoundsaccording to the present invention which may be used to mimic α-helicalproteins in an agonistic or antagonistic manner. In this aspect of thepresent invention, one or more of the compounds according to the presentinvention may be used to mimic or inhibit the binding of an α-helicalprotein for its binding site, whether that binding site is anotherprotein, a receptor (such as a cell surface receptor or a G-proteincoupled receptor), signaling proteins, proteins involved in apoptoticpathways (especially neuronal apoptosis), active sites and regulatorydomains of enzymes, growth factors, DNA, RNA (includingoligonucleotides), viral fusion proteins and viral coat proteins, amongnumerous others. In certain aspects of the present invention, one ormore compound according to the present invention may be used to inhibitthe binding of calmodulin to a calmodulin dependent phosphodiesteraseenzyme (PDE1A, PDE1B or PDE1C).

[0064] In another aspect, the present invention is directed to the useof one or more compounds according to the present invention in apharmaceutically acceptable carrier, additive or excipient at a suitabledose ranging from about 0.05 to about 100 mg/kg of body weight per day,preferably within the range of about 0.1 to 50 mg/kg/day, mostpreferably in the range of 1 to 20 mg/kg/day. The desired dose mayconveniently be presented in a single dose or as divided dosesadministered at appropriate intervals, for example as two, three, fouror more sub-doses per day.

[0065] Ideally, the active ingredient should be administered to achieveeffective peak plasma concentrations of the active compound within therange of from about 0.05 to about 5 uM. This may be achieved, forexample, by the intravenous injection of about a 0.05 to 10% solution ofthe active ingredient, optionally in saline, or orally administered as abolus containing about 1 mg to about 5 g, preferably about 5 mg to about500 mg of the active ingredient, depending upon the active compound andits intended target. Desirable blood levels may be maintained by acontinuous infusion to preferably provide about 0.01 to about 2.0mg/kg/hour or by intermittent infusions containing about 0.05 to about15 mg/kg of the active ingredient. Oral dosages, where applicable, willdepend on the bioavailability of the compounds from the GI tract, aswell as the pharmacokinetics of the compounds to be administered. Whileit is possible that, for use in therapy, a compound of the invention maybe administered as the raw chemical, it is preferable to present theactive ingredient as a pharmaceutical formulation, presented incombination with a pharmaceutically acceptable carrier, excipient oradditive.

[0066] Pharmaceutical formulations include those suitable for oral,rectal, nasal, topical (including buccal and sub-lingual), vaginal orparenteral (including intramuscular, sub-cutaneous and intravenous)administration. Compositions according to the present invention may alsobe presented as a bolus, electuary or paste. Tablets and capsules fororal administration may contain conventional excipients such as bindingagents, fillers, lubricants, disintegrants, or wetting agents. Thetablets may be coated according to methods well known in the art. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may contain conventionaladditives such as suspending agents, emulsifying agents, non-aqueousvehicles (which may include edible oils), or preservatives. Whendesired, the above described formulations may be adapted to providesustained release characteristics of the active ingredient(s) in thecomposition using standard methods well-known in the art.

[0067] In the pharmaceutical aspect according to the present invention,the compound(s) according to the present invention is formulatedpreferably in admixture with a pharmaceutically acceptable carrier. Ingeneral, it is preferable to administer the pharmaceutical compositionorally, but certain formulations may be preferably administeredparenterally and in particular, in intravenously or intramuscular dosageform, as well as via other parenteral routes, such as transdermal,buccal, subcutaneous, suppository or other route. Oral dosage forms arepreferably administered in tablet or capsule (preferably, hard or softgelatin) form. Intravenous and intramuscular formulations are preferablyadministered in sterile saline. Of course, one of ordinary skill in theart may modify the formulations within the teachings of thespecification to provide numerous formulations for a particular route ofadministration without rendering the compositions of the presentinvention unstable or compromising their therapeutic activity.

[0068] In particular, the modification of the present compounds torender them more soluble in water or other vehicle, for example, may beeasily accomplished by minor modifications (such as salt formulation,etc.) which are well within the ordinary skill in the art. It is alsowell within the routineer's skill to modify the route of administrationand dosage regimen of a particular compound in order to manage thepharmacokinetics of the present compounds for maximum beneficial effectto the patient.

[0069] Formulations containing the compounds of the invention may takethe form of solid, semi-solid, lyophilized powder, or liquid dosageforms, such as, for example, tablets, capsules, powders,sustained-release formulations, solutions, suspensions, emulsions,suppositories, creams, ointments, lotions, aerosols or the like,preferably in unit dosage forms suitable for simple administration ofprecise dosages.

[0070] The compositions typically include a conventional pharmaceuticalcarrier or excipient and may additionally include other medicinalagents, carriers, and the like. Preferably, the composition will beabout 0.05% to about 75-80% by weight of a compound or compounds of theinvention, with the remainder consisting of suitable pharmaceuticaladditives, carriers and/or excipients.. For oral administration, suchexcipients include pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharine, talcum, cellulose, glucose,gelatin, sucrose, magnesium carbonate, and the like. If desired, thecomposition may also contain minor amounts of non-toxic auxiliarysubstances such as wetting agents, emulsifying agents, or buffers.

[0071] Liquid compositions can be prepared by dissolving or dispersingthe compounds (about 0.5% to about 20%), and optional pharmaceuticaladditives, in a carrier, such as, for example, aqueous saline, aqueousdextrose, glycerol, or ethanol, to form a solution or suspension. Foruse in oral liquid preparation, the composition may be prepared as asolution, suspension, emulsion, or syrup, being supplied either inliquid form or a dried form suitable for hydration in water or normalsaline.

[0072] When the composition is employed in the form of solidpreparations for oral administration, the preparations may be tablets,granules, powders, capsules or the like. In a tablet formulation, thecomposition is typically formulated with additives, e.g. an excipientsuch as a saccharide or cellulose preparation, a binder such as starchpaste or methyl cellulose, a filler, a disintegrator, and otheradditives typically used in the manufacture of medical preparations.

[0073] An injectable composition for parenteral administration willtypically contain the compound in a suitable i.v. solution, such assterile physiological salt solution. The composition may also beformulated as a suspension in a lipid or phospholipid, in a liposomalsuspension, or in an aqueous emulsion.

[0074] Methods for preparing such dosage forms are known or will beapparent to those skilled in the art; for example, see “Remington'sPharmaceutical Sciences” (17th Ed., Mack Pub. Co, 1985). The compositionto be administered will contain a quantity of the selected compound in apharmaceutically effective amount for effecting increased AMPA receptorcurrents in a subject.

[0075] The person of ordinary skill will take advantage of favorablepharmacokinetic parameters of the pro-drug forms of the presentinvention, where applicable, in delivering the present compounds to apatient suffering from a viral infection to maximize the intended effectof the compound.

[0076] The pharmaceutical compositions according to the invention mayalso contain other active ingredients such as antimicrobial agents,antinfective agents, or preservatives. Effective amounts orconcentrations of each of the active compounds are to be included withinthe pharmaceutical compositions according to the present invention.

[0077] The individual components of such combinations may beadministered either sequentially or simultaneously in separate orcombined pharmaceutical formulations.

[0078] When one or more of the compounds according to the presentinvention is used in combination with a second therapeutic agent activethe dose of each compound may be either the same as or differ from thatwhen the compound is used alone. Appropriate doses will be readilyappreciated by those skilled in the art.

[0079] In method aspects according to the present invention, one or morepharmaceutical compositions according to the present invention may beadministered in the treatment or prevention of any disease state orcondition which is modulated by the interaction of an α-helical proteinwith binding sites for the α-helical protein. Methods for treatingconditions or disease states which are modulated through the binding ofan α-helical protein according to the present invention compriseadministering to a patient in need thereof an effective amount of acompound according to the present invention in an amount and for aduration to treat, resolve, reduce or eliminate the condition or diseasestate. Conditions or disease states which may be treated using compoundsaccording to the present invention include, for example, viralinfections (including Hepatitis B virus (HBV) infections, humanimmunodeficiency virus (HIV) infections or conditions associated withsuch infections (AIDS), Herpes Simplex virus infections (HSV)infections, tumors and/or cancer, proliferative diseases includingpsoriasis, genital warts and hyperproliferative keratinocyte diseasesincluding hyperkeratosis, ichthyosis, keratoderma, lichen planus,hypertension, neuronal disorders so as to promote neuromodulation,asthma, autoimmune diseases including lupus (lupus erythematosus),multiple sclerosis, arthritis, including rheumatoid arthritis, rheumaticdiseases, fibromyalgia, Sjögren's disease and Grave's disease, neuronaldisorders such as ADD, memory loss, learning and language disorders, andneurodegenerative diseases including Alzheimer's disease and Parkinson'sdisease, among others.

[0080] Chemical Synthesis

[0081] Compositions according to the present invention are synthesizedusing the general and synthetic methods which are set forth below.

[0082] General Method

[0083] The invention relates to a method for the formation of syntheticpharmaceutically active agents that are mimics of α-helix structure andfunction. The general embodiment of the invention involves the graftingof essential amino side chain residues from different positions on thesurface of an α-helix onto a synthetic, rigid molecular scaffold thatreproduces the distance and angular orientation of the side chains forfunctional binding to a protein target. The key to the invention is theoriginal design of the synthetic scaffold which exploits a cylindricalshape to provide substitution positions that match the positions of theα-carbon atoms of the amino acids of a peptide or protein sequence in anα-helical conformation. The synthetic scaffold will be chosen from twogroups embodied by the structure

A—X—B—Y—C

[0084] Where A, B and C are substituted aromatic or alicyclic ringslinked either directly or through a connecting bond such as an amide orester group (X, Y=ester or amide).

[0085] General Synthetic Methods

[0086] Two general synthetic routes are envisioned for the two majorembodiments of the invention. The first involves directly linkedsubstituted aromatic and alicyclic ring systems. These are preparedthrough a sequential series of palladium catalyzed coupling reactions ofthe individual monomeric components that are present as theirsubstituted methoxy-halide (or boronate ester) derivatives. In the caseof aromatic ring systems, reaction of the first component with afunctionalized olefin or haloalkane through Heck or related reactionsgives the terminally functionalized A component where W is chosen toenhance electrostatic or hydrophobic interaction to the target proteinor to modulate solubility or pharmacokinetic properties. Deprotection ofthe methoxy group followed by formation of the triflate ester isfollowed by palladium catalyzed reaction (Suzuki, Stille

[0087] or related reaction) with the corresponding substituted methoxyboronate (or halide) derivative of component B (the boronate beingformed directly from the halide derivative) to give the dimericintermediate. Further deprotection of the methoxy group followed byformation of the triflate ester is followed by a second palladiumcatalyzed reaction with the corresponding substituted methoxy boronate(or halide) derivative of component C to give the methoxy-trimerintermediate. Further deprotection of the methoxy group followed byalkylation under basic conditions using a selected alkyl halide V—Br(where V is chosen to enhance electrostatic or hydrophobic interactionto the target protein or to modulate solubility or pharmacokineticproperties) gives the final product. The substituents on the individualcomponents R₁, R₂, and R₃ are chosen to reproduce the recognitionproperties of the key amino acid side chains in an α-helix.

[0088] The synthetic route can be readily modified to permit theinsertion of one or more alicyclic rings into the scaffold framework,either in positions A, B or C. For example, a bis-azo ring system (suchas a substituted piperazine, formed from the corresponding amino acid

[0089] through the intermediacy of the diketopiperazine) is attachedthrough sequential palladium catalyzed aryl amination reactions.

[0090] For those embodiments of the invention that involve aromatic oralicyclic ring systems connected through a linking amide or ester group,a general synthetic sequence is outlined below. The individualsubstituted amino carboxylic acid derivative of component A is protectedthrough a standard amine protecting group (Cbz, Boc, Fmoc, etc. orthrough nitro group reduction) and standard carboxylic acid protectinggroup (orthogonal to the amine e.g. tert.-Butyl, benzyl, trichloroethyl,etc). Deprotection of the carboxylate protecting group followed byreaction with a suitable amine or alcohol (WH, where W is chosen toenhance electrostatic or hydrophobic interaction to the target proteinor to modulate solubility or pharmacokinetic properties) provides theterminally functionalized monomeric components. Amine deprotectionfollowed by reaction with the N-protected carboxylic acid derivative ofsubstituted component B (in the presence of a coupling reagent such asDCC, CDI, BOP) gives the N-protected dimeric derivative. Further aminedeprotection followed by reaction with the N-protected carboxylic acidderivative of substituted component C B (in the presence of a couplingreagent) gives the N-protected trimeric derivative. Further aminedeprotection followed by reaction with a carboxylic acid derivativeV—COOH in the presence of a coupling reagent such as DCC, CDI, BOP)gives the final functionalized trimeric helix mimetic, where W is chosento enhance electrostatic or hydrophobic interaction to the targetprotein or to modulate solubility or pharmacokinetic properties.

[0091] Further embodiments of the conformationally stabilized (foldamer)route to helix mimics is shown in a series of compounds based onpyrrole-4-amino-2-carboxylic acid derivatives (where X=CH),imidazole-4-amino-2-carboxylic acid derivatives (where X=N),thiazole-4-amino-2-carboxylic acid derivatives (where X=S) oroxazole-4-amino2-carboxylic acid derivatives (where X=O). See below,compounds 1a-d. Substituted derivatives of these core scaffolds can beconstructed to reproduce the recognition characteristics of the sidechains of an α-helix (where R¹, R² and R³ are chosen from the group;alkyl, aryl, substituted benzyl, indolyl, hydroxyalkyl,hydroxycarbonylalkyl, thioalkyl etc.) as described earlier. Thesecompounds can be prepared from stepwise condensation of the protectedpyrrole-4-amino-2-carboxylic acid or imidazole-4-amino-2-carboxylic acidprecursors. The synthetic routes to these compounds are embodied in thepreparation of distamycin and netropsin derivatives through stepwisecoupling of amino acid monomers using standard coupling agents. SeeTumet, et al., J.Am. Chem. Soc., 1997, 119, 7636-7644.

[0092] A further embodiment of this appoach involves a mixing of the5-atom heterocycle monomer with the six atom cycle monomers to give aseries of helix mimetics in which the distance and angle between theside chain components is varied. Compounds of this type are exemplifiedas above where two different 5-ring units are linked through a2-substituted-4-aminobenzoic acid derivative (Y=CH) or a2-amino-4-substituted nicotinic group derivative (Y=N). Syntheticprocedures to these compounds follow similar stepwise couplingprocedures in solution or on solid phase as generally described herein.

[0093] A further extension of the terphenyl helix mimetic approachinvolves attachment of additional substituents onto the core terphenylscaffold as set forth in the chemical scheme presented in FIG. 1. Anexample of this class of compounds is shown below. The additionalsubstituent (R₄ in 1 of FIG. 1) functions to reproduce additional aminoacid side chain recognition points within the α-helix being mimicked aswell as modulating the physical properties of the molecule (e.g.solubility). An enabling synthetic route to this class of compounds isshown in FIG. 1 using as an example compound 1 where R₁=Methyl,R₂=methyl, R₃=benzyl and R₄=hydroxycarbonylethyl.

[0094] A further refinement is available from the incorporation ofindane subunit 1I in place of the phenyl derivative in the syntheticsequence which is presented in FIG. 1. 1,6-Disubstituted indanes hadpreviously been shown to be good structural mimics of adjacent residuesin an α-helical conformation. Subunit 1S can be prepared by modificationof published routes and and used the formation of peptidomimetic 1A. Thecalculated structure for 1A shows that it presents a surface containingfeatures of the i, i+4, i+5 and i+7 residues of the (α-helix. Thus, in asmall molecule (<550 M. Wt.) side chain functionality from four of theseven residues involved in almost two turns of an α-helix can beincorporated. Compounds of this type can be readily generated throughstandard aromatic substitution chemistry or modifications of the indaneroutes. In a similar way, helix mimetics based on 1,4-diaryl-2- and8-substituted naphthyl derivatives can be prepared (as in 1B).Similarly, the corresponding N-alkylated indole or 3-substitutedoxindole derivatives, as in 1C and 1D, respectively, provide differentdistance and angular constraints on the side chain mimics of the i, i+4,i+5 and i+7 residues of the iα-helix. In these cases the indane,naphthyl, indole and oxindole components are occupying the centralposition of the helix mimetic. However in all cases the indane,naphthyl, indole and oxindole components can alternatively oradditionally occupy the first and third positions.

[0095] In a further aspect of the present invention, a method ofproducing proteomimetic compounds is contemplated, such methodcomprising providing a cylindrical cage or rigid scaffold compoundaccording to the structure:

W—B—X—B—Y

[0096] Wherein X is selected from the group consisting of a five orsix-membered ring selected from the group consisting of:

[0097]  or a fused ring system selected according to the structure:

[0098] W and Y are each independently selected from the group consistingof

[0099] and each B is independently a connecting bond or an amide orester group connecting W to said X and Y groups;

[0100] said method further comprising identifying chemical groups thatare sterically and electronically similar to the substituents on the αcarbon atoms of natural amino acids and attaching said substituents tounbound atoms on the ring structures of said chemical scaffold, saidsubstituents closely matching the substituents on positions of the αcarbon atoms of a peptide or protein sequence in an α helical protein.In such method, the substituent is selected from the group consisting ofhydrogen, C₁-C₆ alkanol, thioether, mercaptan, benzyl, hydroxybenzyl,C₁-C₆ alkyleneamide, ethyleneamide, C₁-C₆ alkanoic acid, C₁-C₆alkyleneamine, alkylene-1,3-pyrazole, C₁-C₆ alkyleneguanidine and C₁-C₆alkanolamine. In still further aspects of the method, the substitutentis selected from the group consisting of hydrogen (glycine), methyl(alanine), isopropyl (valine), isobutyl (isoleucine), sec-butyl(leucine), benzyl, 4-hydroxybenzyl (from tyrosine), pyrrolidinyl (fromproline), indole (tryptophan), methylmethylenethioether (methionine),methanol (serine), 1-ethanol (threonine), acetate, propionate,methyleneamide (asparagine), ethyleneamide (glutamine), butyleneamine(lysine), propyleneguanidine (arginine), methylenepyrazole (histidinyl)and methylmercaptan (cysteine).

[0101] One of ordinary skill in the art will readily recognize thevariations and modifications which can be made to the general syntheticmethods which have been presented above.

EXAMPLES

[0102] The following examples illustrate but are not intended in any wayto limit the invention.

[0103] All chemicals were obtained from Sigma/Aldrich unless otherwisenoted. All peptides were purchased from the HHMI Biopolymer/KeckFoundation Biotechnology Resource Center at the Yale University Schoolof Medicine (New Haven, Conn.). All solvents were appropriatelydistilled, all glassware was flame dried prior to use and all reactionswere run under an inert (N₂) atmosphere unless otherwise noted. Columnchromatography was performed using silica gel (230-400 mesh) andpreparative thin layer chromatography was completed using 20×20 cm, 1000micron precoated silica gel plates with fluorescent indicator (AnaltechInc., Newark Del.). ¹H NMR spectra were recorded on Bruker AvanceDPX-500 and DPX-400 spectrometers at 500 or 400 MHz. ¹³C NMR spectrawere recorded on a Bruker Avance DPX-500 spectrometer at 125 MHz.Chemical shifts are expressed as parts per million using solvent as theinternal standard. All mass data were obtained from the massspectroscopy facility at the University of Illinios at Urbana Champaignunder the supervision of Dr. Steven Mullen.

[0104] Computation. Computational analysis, where presented, wascompleted using Macromodel (W. C. Still, Columbia). MM2 energyminimizations performed on 3, 2′, 2″-trimethylterphenyl indicate thatthe structure with 55° torsion angles to be the closest of several lowenergy conformers to the structure that presents i, i+4, i+7 side chainmimicry. The six carbon atoms of this conformation corresponding to thethree Cα and the three Cα carbons of the i, i+4, i+7 alanines (yellow inFIG. 2) were overlayed on the helix. The resulting root mean squareddifference (rmsd) between these atoms was calculated to be 0.90 Å.

[0105] Circular Dichroism. CD spectra, where reported, were obtained onan Aviv Dichroism Model 202 spectrometer at 4° C., using a 1 nmbandwith, 1 nm resolution, 0.1 nm path length, and a 5.0 sec averagingtime. Spectra were corrected by the subtraction of a blank correspondingto the solvent composition of each sample. All spectra were recorded inaqueous buffer (50 mM PBS, 150 mM NaCl, pH 7.0). Inhibitor stocksolutions were composed of 1:1 buffer/trifluoroethanol (TFE). OverallTFE concentrations in the experiments never exceeded 0.5%. TFE had noeffect on the CD spectra up to 5% (maximum tested). CD thermaldenaturation experiments were completed by monitoring the Θ222 signalusing a 4-90° C. temperature range with a temperature step of 2 deg/min,dead band value of 0.2, equilibration time of 1 min, and an averagingtime of 30 sec. The T_(m) values for the unfolding transitions wereestimated from the maximum of the first derivative with respect to aplot of CD signal at Θ222 versus T⁻¹.

[0106] The following compounds, as indicated, were synthesized.

[0107] Synthesis Following the Presentation in FIG. 2, Scheme 2

1-(2-methoxyphenyl)-2-methylpropene (9a)

[0108] Isopropyl triphenylphosphonium iodide (5.95 g, 13.7 mmol, 1.5eqv) was suspended in 230 ml of Et₂O at 0° C. n-BuLi (8.6 ml of a 1.6 Msolution in hexanes, 13.7 mmol, 1.5 eqv) was added via syringe. Thesubsequent red solution was allowed to stir for 35 min at rt.2-Methoxybenzaldehyde (9) (1.25 g, 9.18 mmol) in 10 ml of Et₂O was addedvia syringe and the resulting solution was allowed to stir for 20 h atrt. The reaction mixture was filtered. The filtrate was diluted with H₂Oand extracted with Et₂O. The organic fractions were combined, dried(MgSO₄), filtered, and concentrated in vacuo. Column chromatography[Hexanes/Et₂O (9/1)] yielded 0.91 g of a clear oil (61%): ¹H NMR (500MHz, CDCl₃) δ1.82 (s, 3H), 1.94 (s, 3H), 3.85 (s, 3H), 6.32 (s, 1H),6.87 (d, J=8.0 Hz, 1H), 6.63 (t, J=7.5 Hz, 1H), 7.21 (m, 2H); ¹³C NMR(125 MHz, CDCl₃) δ19.50, 26.60, 55.39, 110.27, 120.01, 120.51, 127.33,127.50, 130.42, 135.51, 156.96; HRMS (EI) Calcd for C₁₁H₁₄O: 162.1044.Found 162.1044.

2-isobutylanisole (9b)

[0109] A solution of 1-(2-methoxyphenyl)-2-methylpropene (9a) (3.37 g,20.8 mmol) and 10% Pd/C (300 mg) in 100 ml of anhydrous EtOH at rt washydrogenated at 60 psi until complete conversion was determined by GC/MS(9 h). The reaction mixture was filtered through celite and concentratedin vacuo to yield 2.87 g of a clear oil (84%): ¹H NMR (500 MHz, CDCl₃)δ0.90 (d, J=6.6 Hz, 6H), 1.92 (m, 1H), 2.49 (d, J=7.1 Hz, 2H), 3.82 (s,3H), 6.88 (m, 2H), 7.10 (d, J=8.9 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H); ¹³CNMR (125 MHz, CDCl₃) δ22.55, 28.64, 39.43, 55.22, 110.27, 120.07,126.80, 130.22, 130.80, 157.70; HRMS (EI) Calcd for C₁₁H₁₆O: 164.1201.Found 164.1207.

4-iodo-2-isobutylanisole (10)

[0110] 2-isobutylanisole (9b) (1.5 g, 9.14 mmol),1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (3.24 g, 9.14 mmol, 1.0 eqv) and I₂ (1.18 g, 4.66mmol, 0.51 eqv) were dissolved in 90 ml of CH₃CN. The solution wasstirred for 8 h at rt, diluted with H₂O, and extracted with CH₂Cl₂. Theorganic fractions were combined, dried (MgSO₄), filtered, andconcentrated in vacuo. Column chromatography [Hexanes/CH₂Cl₂ (2/1)]yielded 1.93 g of a clear oil (73%): ¹H NMR (500 MHz, CDCl₃) δ0.89 (d,J=4.3 Hz, 6H), 1.88 (m, 1H), 2.42 (d, J=7.2 Hz, 2H), 3.78 (s, 3H), 6.61(d, J=8.5 Hz, 1H), 7.38 (s, 1H), 7.45 (d, J=10.8 Hz, 1H); ¹³C NMR (125MHz, CDCl₃) δ22.45, 28.64, 39.02, 55.37, 82.58, 112.67, 133.20, 135.61,139.21, 157.72; LRMS (EI) (M+, 290).

2-(3-isobutyl-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(11)

[0111] A solution of 4-iodo-2-isobutylanisole (10) (0.150 g, 0.52 mmol),bis(pinacolato)diboron (0.144 g, 0.57 mmol, 1.1 eqv), KOAc (0.152 g,1.55 mmol, 3 eqv), and PdCl₂dppf (21 mg, 5 mol %) in 3 ml of DMSO wasstirred at 85° C. for 3 h. The mixture was then added to H₂O andextracted with CH₂Cl₂. The organic fractions were combined, backextracted with H₂O, dried (MgSO₄), filtered, and concentrated in vacuo.Column chromatography [Hexanes/EtOAc (9/1)] yielded 0.100 g of a clearoil (67%): ¹H NMR (500 MHz, CDCl₃) δ0.84 (d, J=6.5 Hz, 6H), 1.34 (s,12H), 1.92 (m, 1H), 2.48 (d, J=7 Hz, 2H), 3.84 (s, 3H), 6.84 (d, J=8.5Hz, 1H), 7.54 (s, 1H), 7.66 (d, J=10 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃)δ22.59, 24.86, 28.84, 39.21, 55.15, 83.44, 109.58, 129.56, 134.31,137.38, 160.39; HRMS (EI) Calcd for C₁₇H₂₇BO₃: 290.2053. Found 290.2052.

4-bromo-2-isopropylphenol (12e)

[0112] To a solution of 2-isopropylphenol (12) (2.0 g, 14.6 mmol) in 15ml of Et₂O at 0° C. was added dioxane dibromide (3.62 g, 14.6 mmol, 1eqv). The, solution was allowed to stir for 30 min at rt. The reactionmixture was washed with sat. NaCl and 10% NaHCO₃. The Et₂O phase wasconcentrated in vacuo and then vacuum distilled (142-145° C., 20 mm Hg)to yield 2.07 g of a clear oil (66%) which solidified upon standing: ¹HNMR (500 MHz, CDCl₃) δ1.23 (d, J=3.7 Hz, 6H), 3.16 (m, 1H), 4.84 (s,1H), 6.61 (d, J=8.6 Hz, 1 H), 7.15 (d, J=11.0 Hz, 1H), 7.28 (s, 1H); ¹³CNMR (125 MHz, CDCl₃) δ22.33, 27.17, 113.24, 116.99, 129.34, 129.50,136.91, 151.81; LRMS (EI) (M+, 214/216).

4-bromo-2-isopropylanisole (12f)

[0113] A solution of 4-bromo-2-isopropylphenol (12e) (15.0 g, 69.8mmol), K₂CO₃ (48.2 g, 349 mmol, 5.0 eqv), and CH₃I (99.0 g, 698 mmol,10.0 eqv.) in 200 ml of acetone was refluxed for 24 h. The mixture wasfiltered and concentrated in vacuo. Column chromatography [Hexanes/Et₂O(9/1)] yielded 14.5 g of a clear oil (91%): ¹H NMR (500 MHz, CDCl₃)δ1.18 (d, J=7.0 Hz, 6H), 3.27 (m, 1H), 3.79 (s, 3H), 6.70 (d, J=8.6 Hz,1H), 7.24 (d, J=10.8 Hz, 1H), 7.28 (s, 1H); ¹³C NMR (125 MHz, CDCl₃)δ22.46, 26.74, 55.52, 112.00, 113.02, 129.06, 129.10, 139.38, 155.85;LRMS (EI) (M+, 228/230).

3-(3-isobutyl-4-methoxyphenyl)propanenitrile (10i)

[0114] 4-iodo-2-isobutylanisole (10) (1.92 g, 6.64 mmol), acrylonitrile(0.49 g, 9.29 mmol, 1.4 eqv), tetra-n-butylammonium chloride (1.85 g,6.63 mmol, 1.0 eqv), NaHCO₃ (1.34 g, 15.9 mmol, 2.4 eqv), and Pd(OAc)₂(10 mol %, 150 mg) were dissolved in 10 ml of DMF and the resultingsolution was stirred at 40° C. for 19 h. The mixture was diluted withEt₂O, filtered, and concentrated in vacuo. Column chromatography[Hexanes/EtOAc (4/1)] yielded 1.06 g of a clear oil (74%). GC/MS showeda 2:1 ratio of trans/cis isomers: The oil was dissolved in 40 ml ofanhydrous MeOH and the soln was cooled to 0° C. Mg turnings (4.79 g,19.7 mmol, 40 eqv) were added very slowly and the suspension was allowedto stir for 5 h at rt. The reaction was cooled to 0° C. and 14 ml of 6 MHCl was added very slowly. The mixture was extracted with CHCl₃ and theorganic fractions were combined, dried (MgSO₄), filtered, andconcentrated in vacuo. Column chromatography [Hexanes/EtOAc (5/2)]yielded 1.03 g of a clear oil (96%): ¹H NMR (500 MHz, CDCl₃) δ0.93 (d,J=6.6 Hz, 6H), 1.94 (m, 1H), 2.50 (d, J=7.2 Hz, 2H), 2.58 (t, J=7.4 Hz,2H), 2.89 (t, J=7.4 Hz, 2H), 3.81 (s, 3H), 6.82 (d, J=8.3 Hz, 1H), 6.97(s, 1H), 7.05 (d, J=10.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ19.52,22.40, 28.51, 30.71, 39.28, 55.20, 110.42, 119.16, 126.39, 129.46,130.52, 130.60, 156.76; HRMS (EI) Calcd for C₁₄H₁₉NO: 217.1467. Found217.1468.

3-(4-hydroxy-3-isobutylphenyl)propanenitrile (10j)

[0115] 3-(3-isobutyl-4-methoxyphenyl) propanenitrile (10i) (0.73 g, 3.36mmol) was dissolved in 20 ml of CH₂Cl₂ and cooled to 0° C. BBr₃ (10.1 mlof a 1 M solution in CH₂Cl₂, 10.0 mmol, 3 eqv) was added slowly viasyringe. The solution was allowed to stir for 9 h at 10° C. The reactionmixture was added to H₂O and extracted with CH₂Cl₂. The organicfractions were combined, dried (MgSO₄), filtered, and concentrated invacuo. Column chromatography [Hexanes/EtOAc (2/1)] yielded 0.68 g of aclear oil (99%): ¹H NMR (500 MHz, CDCl₃) δ0.94 (d, J=6.6 Hz, 6H), 1.93(m, 1H), 2.47 (d, J=7.0 Hz, 2H), 2.58 (t, J=7.4 Hz, 2H), 2.87 (t, J=7.4Hz, 2H), 4.64 (s, 1H), 6.73 (d, J=8.8 Hz, 1 H), 6.94 (m, 2H); ¹³C NMR(125 MHz, CDCl₃) δ19.72, 22.50, 28.87, 30.87, 39.26, 115.62, 119.21,126.81, 127.96, 130.09, 131.09, 152.84; HRMS (EI) Calcd for C₁₃H₁₇NO:203.1310. Found 203.1306.

4-(2-cyanoethyl)-2-isobutylphenyltrifluoromethanesulfonate (6)

[0116] 3-(4-hydroxy-3-isobutylphenyl)propanenitrile (10j) (0.67 g, 3.31mmol) was dissolved in 3.5 ml of pyridine and cooled to 0° C. Triflicanhydride (1.12 g, 3.97 mmol, 1.2 eqv) was added slowly via syringe andthe solution was allowed to stir for 17 h at rt. The reaction mixturewas added to H₂O and extracted with Et₂O. The organic fractions werecombined, dried (MgSO₄), filtered, and concentrated in vacuo. Columnchromatography [Hexanes/EtOAc (1/1)] yielded 1.03 g of a clear oil(93%): ¹H NMR (500 MHz, CDCl₃) δ0.94 (d, J=7.3 Hz, 6H), 1.95 (m, 1H),2.58 (d, J=7.2 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 2.97 (t, J=7.3 Hz, 2H),7.17 (m, 2H), 7.25 (d, J=15.4 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ19.17,22.26, 29.17, 30.95, 39.33, 114.83, 117.37, 118.48, 119.91, 121.72,122.46, 127.52, 131.99, 135.01, 138.07, 147.47; HRMS (EI) Calcd forC₁₄H₁₆F₃NO₃S: 335.0803. Found 335.0807.

[0117] Synthesis Following the Presentation in FIG. 11, Scheme 11 andFIG. 3, Scheme 3

[0118]FIG. 11, Scheme 11

3-(2-isobutyl-3′-isopropyl-4′-methoxy-1,1′-biphenyl-4-yl)propanenitrile(6a)

[0119] A solution of 4-bromo-2-isopropylanisole (12f) (6.0 g, 26.2 mmol)in 200 ml of THF was cooled to −78° C. To this solution was added n-BuLi(16.4 ml of 1.6 M solution in hexanes, 26.2 mmol, 1 eqv) via syringe andthe mixture was stirred for 30 min. B(OMe)₃ (8.17 g, 78.6 mmol, 3.0 eqv)was then added and the solution was stirred for 24 h at rt. Water (20ml) and 10% NaOH aq (50 ml) were added and stirring was continued for 1h. The pH was adjusted to 4-5 (1 M HCl) and most of the solvent wasremoved in vacuo. The residue was taken up in EtOAc and the layersseparated. The organic layer was dried (MgSO₄), filtered, andconcentrated in vacuo to yield 4.81 g of a crude solid (95%). Thismaterial was used without further purification. The crude boronic acid(5) (0.081 g, 0.417 mmol, 1.4 eqv), 4-(2-cyanoethyl)-2-isobutylphenyltrifluoromethanesulfonate (6) (0.10 g, 0.30 mmol), and Pd(PPh₃)₄ (10 mol%, 33 mg) were dissolved in 4 ml of 9/1 DME/EtOH. Na₂CO₃ (0.3 ml of 2 Maq solution, 0.59 mmol, 2 eqv) was added via syringe and the solutionwas stirred at 80° C. for 17 h. The reaction mixture was concentrated invacuo and taken up in 2:1 H₂O/CH₂Cl₂. The layers were separated and theH₂O layer was extracted further with CH₂Cl₂. The combined organicfractions were dried (MgSO₄), filtered, and concentrated in vacuo.Column chromatography [Hexanes/EtOAc (3/1)] yielded 0.098 g of a clearoil (98%): ¹H NMR (500 MHz, CDCl₃) δ0.76 (d, J=6.6 Hz, 6H), 1.22 (d,J=6.9 Hz, 6H), 1.69 (m, 1H), 2.48 (d, J=7.2 Hz, 2H), 2.67 (t, J=7.5 Hz,2H), 2.99 (t, J=7.4 Hz, 2H), 3.37 (m, 1H), 3.88 (s, 3H), 6.88 (d, J=8.3Hz, 1H), 7.08 (m, 4H), 7.18 (d, J=7.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃)δ19.39, 22.44, 22.79, 26.65, 29.58, 31.41, 42.26, 55.46, 109.99, 119.18,125.31, 127.26, 127.30, 129.83, 130.76, 133.97, 136.37, 136.50, 140.05,141.61, 155.69; HRMS (EI) Calcd for C₂₃H₂₉NO: 335.2249. Found 335.2252.

3-(4′-hydroxy-2-isobutyl-3′-isopropyl-1,1′-biphenyl-4-yl)propanenitrile(6b)

[0120]3-(2-isobutyl-3′-isopropyl-4′-methoxy-1,1′-biphenyl-4-yl)propanenitrile(6a) (0.56 g, 1.67 mmol) was dissolved in 25 ml of CH₂Cl₂ and cooled to0° C. BBr₃ (5.0 ml of a 1 M solution in CH₂Cl₂, 5.0 mmol, 3 eqv) wasadded slowly via syringe. The solution was allowed to stir for 9 h at10° C. The reaction mixture was added to H₂O and extracted with CH₂Cl₂.The organic fractions were combined, dried (MgSO₄), filtered, andconcentrated in vacuo. Column chromatography [Hexanes/EtOAc (2/1)]yielded 0.49 g of a clear oil (92%): ¹H NMR (500 MHz, CDCl₃) δ0.76 (d,J=6.6 Hz, 6H), 1.26 (d, J=7 Hz, 6H), 1.68 (m, 1H), 2.48 (d, J=7.2 Hz,2H), 2.67 (t, J=7.5 Hz, 2H), 2.98 (t, J=7.4 Hz, 2H), 3.26 (m, 1H), 4.76(s, 1H), 6.78 (d, J=8.1 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 7.09 (m, 3H),7.17 (d, J=7.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ19.39, 22.43, 22.67,27.01, 29.58, 31.39, 42.25, 114.93, 119.17, 125.32, 127.49, 127.61,129.86, 130.73, 133.91, 134.48, 136.42, 140.02, 141.47, 151.60; HRMS(EI) Calcd for C₂₂H₂₇NO: 321.2093. Found 321.2095.

4′-(2-cyanoethyl)-2′-isobutyl-3-isopropyl-1,1′-biphenyl-4-yltrifluoromethanesulfonate (7)

[0121]3-(4′-hydroxy-2-isobutyl-3′-isopropyl-1,1′-biphenyl-4-yl)propanenitrile(6b) (0.48 g, 1.48 mmol) was dissolved in 7.0 ml of pyridine and cooledto 0° C. Triflic anhydride (0.502 g, 1.78 mmol, 1.2 eqv) was addedslowly via syringe and the solution was allowed to stir for 17 h at rt.The reaction mixture was added to H₂O and extracted with Et₂O. Theorganic fractions were combined, dried (MgSO₄), filtered, andconcentrated in vacuo. Column chromatography [Hexanes/EtOAc (3/1)]yielded 0.639 g of a clear oil (95%): ¹H NMR (500 MHz, CDCl₃) δ0.75 (d,J=6.6 Hz, 6H), 1.29 (d, J=6.9 Hz, 6H), 1.64 (m, 1H), 2.45 (d, J=7.2 Hz,2H), 2.68 (t, J=7.4 Hz, 2H), 2.99 (t, J=7.3 Hz, 2H), 3.35 (m, 1H), 7.16(m, 4 H), 7.28 (d, J=8.4 Hz, 1H), 7.31 (s, 1H); ¹³C NMR (125 MHz, CDCl₃)δ19.29, 22.27, 23.07, 27.07, 29.67, 31.22, 42.04, 114.79, 117.32,119.02, 119.87, 120.73, 122.42, 125.57, 128.29, 128.83, 130.07, 130.27,137.40, 139.67, 139.72, 140.64, 142,15, 145.89; HRMS (EI) Calcd forC₂₃H₂₆F₃NO₃S: 453.1586. Found 453.1594.

3-(2,3″-diisobutyl-3′-isopropyl-4″-methoxy-1,1′:4′,1″-terphenyl-4-yl)propanenitrile (7d)

[0122]2-(3-isobutyl-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(11) (0.076 g, 0.26 mmol, 1.2 eqv),4′-(2-cyanoethyl)-2′-isobutyl-3-isopropyl-1,1′-biphenyl-4-yltrifluoromethanesulfonate (7) (0.099 g, 0.22 mmol), and Pd(PPh₃)₄ (15mol %, 37 mg) were dissolved in 4 ml of 9/1 DME/EtOH. Na₂CO₃ (0.22 ml of2 M aq solution, 0.44 mmol, 2 eqv) was added via syringe and thesolution was stirred at 80° C. for 20 h. The reaction mixture wasconcentrated in vacuo and taken up in 2:1 H₂O/CH₂Cl₂. The layers wereseparated and the H₂O layer was extracted further with CH₂Cl₂. Thecombined organic fractions were dried (MgSO₄), filtered, andconcentrated in vacuo. Column chromatography [Hexanes/EtOAc (6/1)]yielded 0.089 g of a clear oil (87%): ¹H NMR (500 MHz, CDCl₃) δ0.79 (d,J=6.6 Hz, 6H), 0.94 (d, J=6.6 Hz, 6H), 1.17 (d, J=6.9 Hz, 6H), 1.74 (m,1H), 1.97 (m, 1H), 2.54 (m, 4H), 2.69 (t, J=7.5 Hz, 2H), 3.01 (t, J=7.4Hz, 2H), 3.17 (m, 1H), 3.88 (s, 3H), 6.91 (d, J=8.3 Hz, 1H), 7.17 (m,8H); ¹³C NMR (125 MHz, CDCl₃) δ19.37, 22.46, 22.58, 24.28, 28.62, 29.37,29.65, 31.44, 39.59, 42.23, 55.39, 109.89, 119.15, 125.38, 126.21,126.69, 127.63, 129.66, 129.79, 129.87, 130.64, 132.06, 133.68, 136.62,139.54, 139.94, 140.52, 141.71, 146.13, 156.72; HRMS (EI) Calcd forC₃₃H₄₁NO: 467.3188. Found 467.3194.

3-(4″-hydroxy-2,3″-diisobutyl-3′-isopropyl-1,1′:4′,1″-terphenyl-4-yl)propanenitrile(8)

[0123]3-(2,3″-diisobutyl-3′-isopropyl-4″-methoxy-1,1′:4′,1″-terphenyl-4-yl)propanenitrile (7d) (0.076 g, 0.16 mmol) was dissolved in 4 ml of CH₂Cl₂ andcooled to 0° C. BBr₃ (0.49 ml of a 1 M solution in CH₂Cl₂, 0.49 mmol,3.0 eqv) was added slowly via syringe. The solution was allowed to stirfor 9 h at 10° C. The reaction mixture was added to H₂O and extractedwith CH₂Cl₂. The organic fractions were combined, dried (MgSO₄),filtered, and concentrated in vacuo. Column chromatography[Hexanes/EtOAc (3/1)] yielded 0.072 g of a clear oil (97%): ¹H NMR (500MHz, CDCl₃) δ0.80 (d, J=6.6 Hz, 6H), 0.99 (d, J=6.6 Hz, 6H), 1.17 (d,J=6.9 Hz, 6H), 1.74 (m, 1H), 2.00 (m, 1H), 2.54 (m, 4H), 2.69 (t, J=7.5Hz, 2H), 3.01 (t, J=7.4 Hz, 2H), 3.16 (m, 1H), 4.70 (s, 1H), 6.83 (d,J=8.6 Hz, 1H), 7.09 (m, 5H), 7.19 (d, J=7.7 Hz, 1H), 7.25 (m, 2H); ¹³CNMR (125 MHz, CDCl₃) δ19.42, 22.46, 22.56, 24.29, 28.81, 29.34, 29.67,31.39, 39.42, 42.17, 114.86, 119.23, 125.39, 126.22, 126.69, 126.89,128.01, 129.75, 129.89, 130.62, 132.33, 134.17, 136.63, 139.31, 139.89,140.55, 141.61, 146.06, 152.58; HRMS (EI) Calcd for C₃₂H₃₉NO: 453.3031.Found 453.3025.

[0124]FIG. 3, Scheme 3

3-[4″-(cyanomethoxy)-2,3″-diisobutyl-3′-isopropyl-1,1′:4′,1″-terphenyl-4-yl]propanenitrile(8f)

[0125] To a solution of3-(4″-hydroxy-2,3″-diisobutyl-3′-isopropyl-1,1′:4′,1″-terphenyl-4-yl)propanenitrile(8) (18.6 mg, 0.04 mmol) and K₂CO₃ (28.0 mg, 0.20 mmol, 5.0 eqv) in 2.0ml of acetone was added ClCH₂CN (31.0 mg, 0.41 mmol, 10.0 eqv) viasyringe. The solution was stirred for 40 h at 55° C. and was then addedto 20 ml of 1:1 H₂O/brine. The mixture was extracted with EtOAc and thecombined organic fractions were washed (brine), dried (MgSO₄), filtered,and concentrated in vacuo. Column chromatography [Hexanes/EtOAc (3/1)]yielded 19.2 mg of a clear oil (95%): ¹H NMR (500 MHz, CDCl₃) δ0.80 (d,J=6.6 Hz, 6H), 0.95 (d, J=6.6 Hz, 6H), 1.18 (d, J=6.8 Hz, 6H), 1.75 (m,1H, 1.95 (m, 1H), 2.55 (m, 4H), 2.70 (t, J=7.5 Hz, 2H), 3.01 (t, J=7.4Hz, 2H), 3.12 (m, 1H), 4.86 (s, 2H), 6.98 (d, J=8.4 Hz, 1H), 7.18 (m,8H); ¹³C NMR (125 MHz, CDCl₃) δ19.43, 22.44, 22.49, 24.27, 28.87, 29.32,29.66, 31.30, 39.27, 42.07, 53.65, 111.09, 115.41, 119.25, 125.39,126.26, 126.73, 127.85, 129.60, 129.89, 130.49, 130.56, 132.76, 136.14,136.65, 138.65, 139.81, 140.79, 141.37, 145.93, 153.58; HRMS (EI) Calcdfor C₃₄H₄₀N₂O: 492.3140. Found 492.3131.

3-[4″-(carboxymethoxy)-2,3″-diisobutyl-3′-isopropyl-1,1′:4′,1″-terphenyl-4-yl]propanoicacid (1a)

[0126]3-[4″-(cyanomethoxy)-2,3″-diisobutyl-3′-isopropyl-1,1′:4′,1″-terphenyl-4-yl]propanenitrile(8f) (19.2 mg, 0.039 mmol) was dissolved in a solution containing 2 mlof 25% NaOH (aq) and 3.5 ml of MeOH. The mixture was stirred at 50° C.for 24 h. The temperature was then reduced to 0° C. and the solution wasacidified to pH 2 with 1N HCl. The mixture was partitioned between EtOAcand brine and the organic layer was separated, dried (MgSO₄), filtered,and concentrated in vacuo. Prep TLC [Hexanes/EtOAc/AcOH (66/33/1)]yielded 15.3 mg of a white solid (74%): ¹H NMR (500 MHz, CDCl₃) δ0.77(d, J=6.6 Hz, 6H), 0.96 (d, J=6.6 Hz, 6H), 1.15 (d, J=6.8 Hz, 6H), 1.72(m, 1H), 2.00 (m, 1H), 2.51 (d, J=7.2 Hz, 2H), 2.60 (d, J=7.1 Hz, 2H),2.77 (t, J=7.6 Hz, 2H), 3.01 (t, J=7.4 Hz, 2H), 3.12 (m, 1H), 4.75 (s,2H), 6.79 (d, J=8.9 Hz, 1H), 7.13 (m, 8H); ¹³C NMR (125 MHz, CDCl₃)δ22.44, 22.57, 24.31, 28.78, 29.36, 29.65, 30.29, 35.33, 39.58, 42.17,65.23, 110.89, 125.49, 126.32, 126.75, 126.83, 127.82, 129.67, 130.08,130.26, 132.59, 135.28, 138.67, 138.81, 139.40, 140.64, 140.94, 145.90,154.48, 172.99, 177.73; HRMS (EI) Calcd for C₃₄H₄₂O₅: 530.3032. Found530.3031.

[0127] Synthesis Following the Presentation in FIG. 3, Scheme 3

3-[4″-(2-aminoethoxy)-2,3″-diisobutyl-3′-isopropyl-1,1′:4′,1″-terphenyl-4-yl]propan-1-aminedihydrochloride (2)

[0128]3-[4″-(cyanomethoxy)-2,3″-diisobutyl-3′-isopropyl-1,1′:4′,1″-terphenyl-4-yl]propanenitrile(8f) (19.0 mg, 0.038 mmol) was dissolved in 5 ml of EtOH containing 10%Pd/C (15 mg) and 0.1 ml HCl (cone.). The solution was stirred overnightunder 20 psi of H₂. The reaction mixture was filtered through celite andthe filtrate was concentrated in vacuo to yield 20 mg of a white solid(91%): ¹H NMR (500 MHz, CD₃OD) δ0.75 (d, J=6.6 Hz, 6H), 0.93 (d, J=6.9Hz, 6H), 1.14 (d, J=6.9, 6H), 1.68 (m, 2H), 1.96 (m, 1H), 1.99 (m, 1H),2.54 (d, J=6.6 Hz, 2H), 2.62 (d, J=6.9 Hz, 2H), 2.76 (t, J=7.4, 2H),2.96 (t, J=6.8 Hz, 2H), 3.11 (m, 1H), 3.41 (t, J=4.5 Hz, 2H), 4.29 (t,J=5.0 Hz, 2H), 7.13 (m, 9H); ¹³C NMR (125 MHz, CD₃OD) δ22.85, 22.96,24.61, 30.15, 30.53, 30.54, 30.81, 33.34, 40.12, 40.53, 40.70, 43.42,66.06, 112.90, 126.84, 127.50, 127.67, 129.06, 130.75, 131.25, 131.29,131.33, 133.29, 136.26, 140.46, 140.49, 140.59, 141.95, 142.56, 147.13,156.52; HRMS (FAB, M+H) Calcd for C₃₄H₄₉N₂O: 501.3845. Found 501.3845.

Methyl-3-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)propanoate (13b)

[0129] Methyl 3-(4-hydroxyphenyl)propanoate (13) (1.0 g, 5.5 mmol) wasdissolved in 5 ml of pyridine at 0° C. Triflic anhydride (1.1 ml, 6.6mmol, 1.2 eqv) was added and the solution was allowed to stir for 48 hat rt. The reaction mixture was added to H₂O and extracted with Et₂O.The organic fractions were combined, dried (MgSO₄), filtered, andconcentrated in vacuo. Column chromatography [Hexanes/EtOAc (2/1)]yielded 1.60 g of a clear oil (92%): ¹H NMR (400 MHz, CDCl₃) δ2.64 (t,J=8.0 Hz, 2H), 2.98 (t, J=7.2 Hz, 2H), 3.67 (s, 3H), 7.19 (d, J=8.8 Hz,2H), 7.28 (d, J=8.4 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ30.12, 35.20,51.66, 114.88, 117.43, 119.98, 121.29, 122.53, 130.07, 141.10, 148.04,172.77; HRMS (EI) Calcd for C₁₁H₁₁F₃O₅S: 312.0279. Found 312.0275.

Bis methyl 3-(1,1′:4′,1″-terphenyl-4,4″-yl)propanoate (13c)

[0130] Methyl-3-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)propanoate(13b) (188 mg, 0.60 mmol, 2.0 eqv), 1,4-phenylenebisboronic acid (50 mg,0.30 mmol), and Pd(PPh₃)₄ (30 mol %, 100 mg) were dissolved in 7 ml of6/1 DME/EtOH. Na₂CO₃ (0.6 ml of 2 M aq solution, 1.2 mmol, 4.0 eqv) wasadded via syringe and the solution was stirred at 80° C. for 36 h. Thereaction mixture was concentrated in vacuo. Column chromatography[Hexanes/EtOAc/CH₂Cl₂ (2/1/1)] yielded 0.095 g of a white solid (79%):¹H NMR (400 MHz, CDCl₃) δ2.55 (t, J=8.0 Hz, 4H), 2.88 (t, J=7.2 Hz, 4H),3.56 (s, 6H), 7.16 (d, J=8.0 Hz, 4H), 7.43 (d, J=7.6 Hz, 4H), 7.52 (s,4H); ¹³C NMR (125 MHz, CDCl₃) δ30.54, 35.59, 51.64, 127.07, 127.28,128.73, 138.68, 139.64, 139.66, 173.29; HRMS (EI) Calcd for C₂₆H₂₆O₄:402.1831. Found 402.1832.

Bis methyl 3-(1,1′:4′,1″-terphenyl-4,4″-yl)propanoic acid (3)

[0131] Bis methyl 3-(1,1′:4′,1″-terphenyl-4,4″-yl)propanoate (13c) (23mg, 0.06 mmol) was dissolved in 5 ml of a 3/1/1 mixture ofdioxane/HMPA/H₂O. NaOH (0.3 ml of a 25% aq solution) was added and themixture was stirred at 110° C. for 2 h. The reaction was cooled to rt,added to H₂O, and acidified to pH 1.0 with 1 N HCl. The mixture wasextracted with EtOAc and the organics were combined, washed with H₂O,dried (MgSO₄), filtered, and concentrated in vacuo. The resulting solidwas washed several times with CH₂Cl₂ and then sufficiently dried toyield 20 mg of the purified product as a white solid (95%): ¹H NMR (400MHz, DMSO) δ2.58 (t, J=7.6 Hz, 4H), 2.87 (t, J=7.2 Hz, 4H), 7.34 (d, J=8Hz, 4H), 7.63 (d, J=8 Hz, 4H), 7.73 (s, 4H); ¹³C NMR (125 MHz, DMSO)δ29.86, 34.99, 126.35, 126.84, 128.79, 137.27, 138.68, 140.15, 173.64;LRMS (ESI) (M+, 374.4).

(4-iodophenoxy)acetonitrile (14e)

[0132] 4-iodophenol (14) (2.0 g, 9.1 mmol), chloroacetonitrile (5.75 ml,91 mmol, 10 eqv), and K₂CO₃ (6.28 g, 45.5 mmol, 5 eqv) were added to 20ml of acetone. The mixture was stirred at 45° C. for 24 h. The mixturewas then added to 1/1 H₂O/brine and extracted with EtOAc. The organicswere combined, washed with brine, dried (MgSO₄), filtered, andconcentrated in vacuo. Column chromatography [Hexanes/EtOAc (2/1)]yielded 1.55 g of a white solid (66%): ¹H NMR (400 MHz, CDCl₃) δ4.74 (s,2H), 6.77 (d, J=7.2 Hz, 2H), 7.64 (d, J=7.2 Hz, 2H); ¹³C NMR (125 MHz,CDCl₃) δ53.59, 85,85, 114.69, 117.25, 138.74, 156.38; HRMS (EI) Calcdfor C₈H₆INO: 258.9494. Found 258.9505.

[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetonitrile(15)

[0133] A solution of (4-iodophenoxy)acetonitrile (14e) (0.30 g, 1.16mmol), bis(pinacolato)diboron (0.32 g, 1.27 mmol, 1.1 eqv), KOAc (0.34g, 3.47 mmol, 3.0 eqv), and PdCl₂dppf (5 mol %, 47 mg) in 4 ml of DMSOwas stirred at 85° C. for 16 h. The mixture was added to H₂O andextracted with CH₂Cl₂. The organic fractions were combined, backextracted with H₂O, dried (MgSO₄), filtered, and concentrated in vacuo.Column chromatography [Hexanes/EtOAc (2/1)] yielded 0.241 g of a whitesolid (80%): ¹H NMR (400 MHz, CDCl₃) δ1.34 (s, 12H), 4.79 (s, 2H), 6.97(d, J=8.4 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃)δ24.85, 53.18, 83.80, 114.03, 114.89, 136.79, 158.89; HRMS (EI) Calcdfor C₁₄H₁₈BNO₃: 258.1416. Found 258.1412.

3-[4′-(carboxymethoxy)-1,1′-biphenyl-4-yl)propanoic acid (4)

[0134][4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetonitrile(15) (55 mg, 0.21 mmol), 4-bromophenylhydrocinnamonitrile (44 mg, 0.21mmol, 1 eqv), and Pd(PPh₃)₄ (5 mol %, 12 mg) were dissolved in 3 ml ofDME. Na₂CO₃ (0.21 ml of 2 M aq solution, 0.42 mmol, 2 eqv) was added viasyringe and the solution was stirred at 80° C. for 20 h. The reactionmixture was concentrated in vacuo and taken up in 2:1 H₂O/CH₂Cl₂. Thelayers were separated and the water layer was extracted further withCH₂Cl₂. The combined organic fractions were dried (MgSO₄), filtered, andconcentrated in vacuo to yield a white solid. The crude solid wasdissolved in 3/1 MeOH/dioxane. NaOH (1.5 ml of a 25% aq solution) wasadded and the mixture was stirred vigorously at 50° C. for 24 h. Thesolution was acidified to pH 1.0 with 1N HCl and extracted with EtOAcseveral times. The organics were combined, dried (MgSO₄), filtered, andconcentrated in vacuo to yield a white solid. This material was washedseveral times with CH₂Cl₂ to yield 59 mg of purified product (93%): ¹HNMR (400 MHz, DMSO) δ2.56 (t, J=7.2 Hz, 2H), 2.84 (t, J=7.2 Hz, 2H),4.71 (s, 2H), 6.98 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.52 (d,J=8.0 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H); ¹³C NMR (125 MHz, DMSO) δ29.84,35.07, 64.41, 114.75, 126.05, 127.46, 128.69, 132.66, 137.42, 139.37,157.13, 170.10, 173.68; HRMS (EI) Calcd for C₁₇H₁₆O₅: 300.0998. Found300.1003.

[0135] Synthesis Following the Presentation in FIG. 4, Scheme 4

5-Bromo-2-methoxy-benzoic acid (17)

[0136] 6.42 ml (125 mmol, 1.1 eqv) Br₂ was added to a solution of 17.50g (115 mmol) 2-Methoxy-benzoic acid (16) in 220 ml CH₂Cl₂/H₂O (1:1) andthe resulting mixture was stirred at rt for 19 h. After adding 1.32 gNaHSO₃ (12.7 mmol, 0.11 eq) the aq. layer was extracted with CH₂Cl₂. Thecomb. org. fractions were dried over MgSO₄ and the solvent wasevaporated. The resulting white solid was suspended in 45 ml CH₂Cl₂ andtreated with 450 ml ice-cold hexanes. The obtained white residue wasfiltered, washed with ice-cold hexanes and dried in high vacuum. Thisled to 24.53 g (106 mmol, 92%) 17: ¹H NMR (500 MHz, CDCl₃) δ4.10 (s,3H), 6.96 (d, 1H, J=8.83 Hz), 7.67 (dd, 1H, J₁=8.83 Hz, J₂=2.52 Hz),8.31 (d, 1H, J=2.68 Hz), 11.91 (s, 1H), 10.50 (s, br., 1H).

(5-bromo-2-hydroxy-phenyl)-phenyl-methanone (18)

[0137] 10.07 ml (138.8 mmol, 2.2 eqv) SOCl₂ was added to a solution of14.77 g (63.9 mmol) 5-Bromo-2-methoxy-benzoic acid (17) in 140 ml drytoluene, followed by 0.5 ml (6.5 mmol, 0.1 eqv) DMF. After stirring thissolution for 1.5 h at 70° C. the solvent was evaporated and the thecrude acyl chloride was dissolved in 75 ml of dry benzene. This solutionwas then added cautiously under stirring to a suspension of 10.30 g(77.3 mmol, 1.2 eqv) AlCl₃ in 80 ml dry benzene at 10° C. After completeaddition the resulting mixture was refluxed for 5 h and then quenched byadding H₂O and conc. hydrochloric acid. The aq. layer was extracted withEtOAc and the comb. org. fractions were dried over NaSO₄ and evaporated.Column chromatography (CH₂Cl₂) yielded 16.03 g (57.9 mmol, 90%) 18 as ayellow solid: R_(f) (CH₂Cl₂) 0.67; ¹H NMR (500 MHz, CDCl₃) δ6.99 (d, 1H,J=8.99 Hz), 7.52-7.68 (m, 6H), 7.70 (d, 1H, J=2.36 Hz), 11.91 (s, 1H);LRMS (EI) m/z 278 (80), 277 (100), 276 (86), 275 (92), 201 (31), 200(22), 199 (30) 198 (20), 105 (63), 77 (57), 63 (19); HRMS (EI) Calcd.for C₁₃H₉BrO₂: 275.978591. Found: 275.977717.

4-bromo-2-(hydroxy-phenyl-methyl)-phenol (19)

[0138] 1.02 g (27 mmol, 3.9 eqv) NaBH₄ was added cautiously at rt to asolution of 1.92 g (6.9 mmol)(5-Bromo-2-hydroxy-phenyl)-phenyl-methanone (18) in 70 ml dry MeOH.After stirring this solution for 2 h at rt the solvent was evaporatedand the residue was taken up in 70 ml water and 70 ml Et₂O. The aq.layer was extracted with Et₂O and the comb. org. fractions were washedtwice with water, dried over Na₂SO₄ and evaporated. Columnchromatography (Hexanes/EtOAc (1+1)) yielded 1.88 g (6.7 mmol, 98%) 19as a white solid: R_(f) (Hexanes/EtOAc (1+1)) 0.57; mp 96-97° C.; ¹H NMR(500 MHz, CDCl₃) δ2.76 (d, 1H, J=3.15 Hz), 5.98 (d, 1H, J=3.00 Hz), 6.79(d, 1H, J=8.67 Hz), 6.98 (dd, 1H, J₁=2.21 Hz, J₂=0.47 Hz), 7.28 (dd, 1H,J₁=8.67 Hz, J₂=2.36 Hz), 7.33-7.41 (m, 5H), 7.92 (s, 1H); LRMS (EI) m/z278 (5), 276 (4), 262 (56), 261 (100), 260 (46), 259 (95), 181 (21), 180(12), 153 (12), 152 (33), 77 (16), 76 (16), 63 (10); HRMS (EI) Calcd.for C₁₃H₁₁BrO₂: 277.994241. Found: 277.993366.

2-benzyl-4-bromo-phenol (20)

[0139] A solution of 13.24 g (99.3 mmol, 4.1 eqv) AlCl₃ in 85 ml dryEt₂O was added cautiously under stirring to a suspension of 3.91 g(102.9 mmol, 4.2 eqv) LiAlH₄ in 100 ml dry Et₂O. After complete additionthe resulting mixture was stirred for 30 min at rt and then a solutionof 6.85 g (24.5 mmol) 4-Bromo-2-(hydroxy-phenyl-methyl)-phenol (19) in80 ml dry Et₂O was added dropwise. The mixture was refluxed for 12 h andafter that cooled to 0° C. After adding cautiously 60 ml of a mixture ofEt₂O/MeOH (1:1), 170 ml 1 N HCl-solution was added and the mixture wasextracted with Et₂O. The comb. org. fractions were washed with brine,dried over Na₂SO₄ and evaporated. Column chromatography (CH₂Cl₂) yielded4.00 g (15.2 mmol, 62%) 20 as a colorless liquid: R_(f) (CH₂Cl₂) 0.41;¹H NMR (500 MHz, CDCl₃) δ3.95 (s, 2H), 4.64 (s, 1H), 6.67 (dd, 1H,J₁=8.04 Hz, J₂=0.79 Hz), 7.23 (m, 5H), 7.31 (m, 2H); LRMS (EI) m/z 265(17), 264 (98), 263 (21), 262 (100), 186 (53), 184 (49), 183 (78), 182(18), 181 (27), 165 (49), 153 (23), 152 (26), 91 (29), 84 (14), 78 (25),77 (31), 76 (16), 63 (15); HRMS (EI) Calcd. for C₁₃H₁₁BrO: 261.999326.Found: 261.998568.

2-benzyl-4-bromo-anisole (21)

[0140] 9.48 ml (152 mmol, 10 eqv) iodomethane was added to a suspensionof 4.00 g (15.2 mmol) 2-Benzyl-4-bromo-phenol (20) and 10.50 g (76 mmol,5 eqv) K₂CO₃ in 70 ml acetone and the resulting mixture was refluxed for24 h. After adding water and aq. NH₃-solution, the aq. layer wasextracted with Et₂O. The comb. org. fractions were washed with brine,dried over Na₂SO₄ and evaporated. Column chromatography (CH₂Cl₂) yielded4.11 g (14.8 mmol, 98%) 21 as a colorless liquid: R_(f) (CH₂Cl₂) 0.77;¹H NMR (400 MHz, CDCl₃) δ3.79 (s, 3H), 3.92 (s, 2H), 6.72 (d, 1H, J=8.59Hz), 7.18 (m, 4H), 7.27 (m, 3H); LRMS (EI) m/z 279 (17), 278 (95), 277(18), 276 (96), 263 (14), 261 (17), 198 (18), 197 (65), 182 (34), 181(31), 166 (20), 165 (56), 154 (19), 153 (24), 152 (29), 92 (11), 91(100), 77 (13), 76 (16), 63 (13); HRMS (EI) Calcd. for C₁₄H₁₃BrO:276.014976. Found: 276.014234.

3-benzyl-4-methoxy-benzene-1-boronic acid (22)

[0141] 8.61 ml (13.8 mmol, 1 eqv) of a 1.6 M solution of n-BuLi inhexanes was added to a solution of 3.82 g (13.8 mmol)2-Benzyl-4-bromo-anisol (21) in 100 ml dry THF at −78° C. After stirringthis mixture for 30 min at −78° C., 4.70 ml (41.4 mmol, 3 eqv) B(OMe)₃was added and the solution was stirred for 24 h at rt. Now 10 ml waterand 25 ml of a 10% aq. NaOH-solution were added and stirring wascontinued for further 60 min. Then the pH was adjusted to 4-5 with1-N-HCl-solution and most of the solvent was evaporated. The residue wasextracted with EtOAc and the comb. org. fractions were dried over MgSO₄and evaporated, which led after drying in high vacuum to 3.33 g (13.8mmol, 100%) of an orange solid. This crude boronic acid 22 was usedwithout further purification: ¹H NMR (500 MHz, CDCl₃) δ3.81 (s, 3H),3.98 (s, 2H), 6.89 (d, 1H, J=8.20 Hz), 7.10-7.23 (m, 5H), 7.79 (d, 1H,J=1.58 Hz), 7.96 (dd, 1H, J₁=8.20 Hz, J₂=1.73 Hz).

2-(3-benzyl-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(23)

[0142] A solution of 250.7 mg (0.91 mmol) 2-Benzyl-4-bromo-anisole (21),243.1 mg (0.96 mmol, 1.1 eqv) bis(pinacolato)diboron, 269.3 mg (2.74mmol, 3 eqv) KOAc and 37.7 mg (46 μmol, 0.05 eqv) PdCl₂dppf*CH₂Cl₂ in 5ml DMSO was heated at 85° C. for 3 h. After that, water was added andthe mixture was extracted with CH₂Cl₂. The comb. org. fractions werewashed with water, dried over MgSO₄ and evaporated. Columnchromatography (Hexanes/EtOAc (9+1)) yielded 160 mg (0.49 mmol, 55%) 23as a white solid: R_(f) (Hexanes/EtOAc (9+1)) 0.22; ¹H NMR (400 MHz,CDCl₃) δ1.26 (s, 12H), 3.74 (s, 3H), 3.90 (s, 2H), 6.80 (d, 1H, J=8.21Hz), 7.05-7.24 (m, 5H), 7.57 (d, 1H, J=1.64 Hz), 7.62 (dd, 1H, J₁=8.21Hz, J₂=1.64 Hz); LRMS (EI) m/z 325 (24), 324 (100), 323 (28), 309 (18),238 (21), 225 (33), 224 (36), 223 (12), 209 (16), 191 (9), 165 (20), 147(14), 117 (10), 91 (15), 83 (10); HRMS (EI) Calcd. for C₂₀H₂₅BO₃:324.189675. Found: 324.188981.

3-(3′-benzyl-2-isobutyl-4′-methoxy-1,1′-biphenyl-4-yl)propanenitrile(24)

[0143] 490 mg (1.46 mmol) Trifluoro-methanesulfonic acid4-(2-Cyanoethyl)-2-isobutyl-phenyl ester (6), 505 mg (2.09 mmol, 1.4eqv) crude 3-Benzyl-4-methoxy-benzene-1-boronic acid (22) and 169.4 mg(0.15 mmol, 0.1 eqv) Pd(Ph₃P)₄ were dissolved in 20 ml DME/EtOH (9+1).1.46 ml (2.92 mmol, 2 eqv) of a 2 M aq. Na₂CO₃-solution was added tothis yellow solution and the resulting mixture was heated at 80° C. for17 h. After concentrating the mixture in vacuo the residue was taken upin water and extracted with CH₂Cl₂. The comb. org. fractions were driedover MgSO₄ and evaporated. Column chromatography (Hexanes/EtOAc (3+1))yielded 290.8 mg (0.76 mmol, 52%) 24 as a clear oil: R_(f)(Hexanes/EtOAc (3+1)) 0.34; ¹H NMR (400 MHz, CDCl₃) δ0.63 (d, 6H, J=6.70Hz), 1.55 (m, 1H), 2.35 (d, 2H, J=7.33 Hz), 2.57 (t, 2H, J=7.45 Hz),2.88 (t, 2H, J=7.45 Hz), 3.79 (s, 3H), 3.92 (s, 2H), 6.82 (d, 1H, J=8.34Hz), 6.92 (d, 1H, J=2.15 Hz), 6.96-7.20 (m, 9H); LRMS (EI) m/z 383 (13),335 (15), 293 (23), 214 (17), 187 (21), 161 (20), 160 (100), 145 (35),144 (35), 105 (50), 91 (58), 77 (11); HRMS (EI) Calcd. for C₂₇H₂₉NO:383.224914. Found: 383.225267.

3-(3′-benzyl-4′-hydroxy-2-isobutyl-1,1′-biphenyl-4-yl)propanenitrile(25)

[0144] 2.20 ml (2.20 mmol, 3 eqv) of a 1 M solution of BBr₃ in CH₂Cl₂was added to a solution of 279 mg (0.73 mmol)3-(3′-Benzyl-2-isobutyl-4′-methoxy-1,1′-biphenyl-4-yl)propanenitrile(24) in 12 ml dry CH₂Cl₂ at 0° C. via syringe. After that, the solutionwas stirred for 2 h at 0° C. and then for 7 h at rt. The reactionmixture was then added to water and extracted with CH₂Cl₂. The comb.org. fractions were dried over MgSO₄ and evaporated. Columnchromatography, (Hexanes/EtOAc (2+1)) yielded 258.5 mg (0.70 mmol, 96%)25 as a pale yellow oil: R_(f) (Hexanes/EtOAc (2+1)) 0.53; ¹H NMR (500MHz, CDCl₃) δ0.65 (d, 6H, J=6.62 Hz), 1.57 (m, 1H), 2.38 (d, 2H, J=7.25Hz), 2.57 (t, 2H, J=7.41 Hz), 2.89 (t, 2H, J=7.41 Hz), 3.95 (s, 2H),4.62 (s, br., 1H), 6.74 (d, 1H, J=8.04 Hz), 6.94-7.24 (m, 10H); LRMS(EI) m/z 369 (8), 335 (10), 293 (15), 161 (13), 160 (66), 91 (35), 86(63), 84 (100); HRMS (EI) Calcd. for C₂₆H₂₇NO: 369.209264. Found:369.209026.

Trifluoro-methanesulfouic acid3-benzyl-4′-(2-cyano-ethyl)-2′-isobutyl-biphenyl-4-yl ester (26)

[0145] 0.10 ml (0.59 mmol, 1.8 eqv) triflic anhydride was added to asolution of 116.8 mg (0.32 mmol)3-(3′-Benzyl-4′-hydroxy-2-Isobutyl-1,1′-biphenyl-4-yl)propanenitrile(25) in 5 ml pyridine at 0° C. The resulting mixture was stirred at 0°C. for 30 min and then at rt for 18 h. After that, water was added andthe mixture was extracted with Et₂O. The comb. org. fractions werewashed with brine, dried over MgSO₄ and evaporated. Columnchromatography (Hexanes/EtOAc (1+1)) yielded 136.9 mg (0.27 mmol, 85%)26 as a pale violet solid: R_(f) (Hexanes/EtOAc (1+1)) 0.59, ¹H NMR (500MHz, CDCl₃) δ0.64 (d, 6H, J=6.62 Hz), 1.51 (m, 1H), 2.31 (d, 2H, J=7.25Hz), 2.61 (t, 2H, J=7.41 Hz), 2.93 (t, 2H, J=7.41 Hz), 4.07 (s, 2H),7.03-7.08 (m, 4H), 7.13-7.21 (m, 4H), 7.24-7.31 (m, 3H); LRMS (EI) m/z503 (10), 502 (36), 501 (100), 369 (17), 368 (45), 326 (14), 91 (43);HRMS (EI) Calcd. for C₂₇H₂₆F₃NO₃S: 501.158551. Found: 501.158983.

3-(3′,3″-dibenzyl-2-isobutyl-4″-methoxy-1,1′:4′,1″-terphenyl-4-yl)propanenitrile(27)

[0146] 167.7 mg (0.33 mmol)4′-(2-Cyanoethyl)-3-benzyl-2′-isobutyl-1,1′-biphenyl-4-yl-trifluoromethanesulfonate(26), 158.7 mg (0.49 mmol, 1.5 eqv)2-(3-Benzyl-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(23) and 58.8 mg (50.9 μmol, 0.15 eqv) Pd(Ph₃P)₄ were dissolved in 10 mlDME/EtOH (9+1). 0.33 ml (0.66 mmol, 2 eqv) of a 2 M aq. Na₂CO₃-solutionwas added to this yellow solution and the resulting mixture was heatedat 80° C. for 8 h. After concentrating the mixture in vacuo the residuewas taken up in water and extracted with CH₂Cl₂. The comb. org.fractions were dried over MgSO₄ and evaporated. Column chromatography(Hexanes/EtOAc (3+1)) yielded 165.6 mg (0.30 mmol, 91%) (27) as a clearoil: R_(f) (Hexanes/EtOAc (3+1)) 0.30; ¹H NMR (500 MHz, CDCl₃) δ0.69 (d,6H, J=6.62 Hz), 1.63 (m, 1H), 2.43 (d, 2H, J=7.41 Hz), 2.61 (t, 2H,J=7.57 Hz), 2.93 (t, 2H, J=7.57 Hz), 3.82 (s, 3H), 3.93 (s, 4H), 6.85(d, 1H, J=8.36 Hz), 6.94 (m, 2H), 7.02-7.22 (m, 16H); LRMS (EI) m/z 549(3), 501 (2), 446 (11), 383 (5), 335 (6), 293 (9), 256 (14), 215 (16),214 (100), 199 (16), 160 (49), 91 (47); HRMS (EI) Calcd. for C₄₀H₃₉NO:549.303164. Found: 549.302298.

3-(3′,3″-dibenzyl-4″-hydroxy-2-isobutyl-1,1″:4″,1″-terphenyl-4-yl)propanenitrile(28)

[0147] 0.90 ml (0.90 mmol, 3 eqv) of a 1 M solution of BBr₃ in CH₂Cl₂was added to a solution of 164.3 mg (0.30 mmol)3-(3′,3″-Dibenzyl-2-isobutyl-4″-methoxy-1,1′:4′,1″-terphenyl-4-yl)propanenitrile(27) in 7 ml dry CH₂Cl₂ at 0° C. via syringe. After that, the solutionwas stirred for 2 h at 0° C. and then for 4 h at rt. The reactionmixture was then added to water and extracted with CH₂Cl₂. The comb.org. fractions were dried over MgSO₄ and evaporated. Columnchromatography (Hexanes/EtOAc (2+1)) yielded 137.5 mg (0.26 mmol, 86%)28 as a colorless oil: R_(f) (Hexanes/EtOAc (2+1)) 0.35; ¹H NMR (500MHz, CDCl₃) δ0.67 (d, 6H, J=6.62 Hz), 1.61 (m, 1H), 2.40 (d, 2H, J=7.09Hz), 2.58 (t, 2H, J=7.41 Hz), 2.91 (t, 2H, J=7.41 Hz), 3.89 (s, 2H),3.93 (s, 2H), 5.57 (s, 1H), 6.74 (d, 1H, J=8.04 Hz), 6.90 (m, 2H),6.99-7.26 (m, 16H); LRMS (EI) m/z 536 (19), 535 (46), 501 (10), 446 (9),369 (21), 91 (100), 78 (12), 76 (10); HRMS (EI) Calcd. for C₃₉H₃₇NO:535.287514. Found: 535.287420.

3-(3′,3″-dibenzyl-4″-(cyanomethoxy)-2-isobutyl-1,1′:4′,1″-terphenyl-4-yl)propanenitrile(29)

[0148] To a suspension of 136.8 mg (0.26 mmol)3-(3′,3″-Dibenzyl-4″-hydroxy-2-isobutyl-1,1′:4′,1″-terphenyl-4-yl)propanenitrile(28) and 184.9 mg (1.34 mmol, 5.2 eqv) K₂CO₃ in 12 ml acetone, 0.17 ml(2.69 mmol, 10.3 eqv) chloroacetonitrile was added. The resultingmixture was stirred for 40 h at 55° C. and then added to 40 ml of amixture of brine/water (1+1). After extraction with EtOAc the combinedorg. fractions were washed with brine, dried over MgSO₄ and evaporated.Column chromatography (Hexanes/EtOAc (2+1)) yielded 144.9 mg (0.25 mmol,97%) 29 as a colorless oil: R_(f) (Hexanes/EtOAc (2+1)) 0.33; ¹H NMR(500 MHz, CDCl₃) δ0.70 (d, 6H, J=6.62 Hz), 1.64 (m, 1H), 2.44 (d, 2H,J=7.41 Hz), 2.62 (t, 2H, J=7.41 Hz), 2.94 (t, 2H, J=7.41 Hz), 3.92 (s,2H), 3.94 (s, 2H), 4.71 (s, 2H), 6.92 (m, 3H), 7.03-7.18 (m, 14H),7.20-7.26 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ19.38, 21.04, 22.39, 29.53,31.33, 35.96, 39.11, 42.02, 53.96, 111.86, 115.18, 119.18, 125.39,125.79, 126.07, 127.27, 128.27, 128.41, 128.52, 128.64, 128.76, 129.86,129.94, 130.31, 130.55, 131.64, 132.33, 136.32, 136.78, 137.69, 139.77,140.19, 140.88, 140.89, 141.40, 149.00, 153.60; LRMS (EI) m/z 575 (2),574 (5), 535 (1), 501 (1), 446 (2), 409 (15), 408 (50), 369 (13), 91(100); HRMS (EI) Calcd. for C₄₁H₃₈N₂O: 574.298413. Found: 574.298309.

3-(3′,3″-dibenzyl-4″-(carboxymethoxy)-2-isobutyl-1,1′:4′,1″-terphenyl-4-yl)propanoicacid (1b)

[0149] 5 ml (41.5 mmol, 178 eqv) of a 25% aq. NaOH-solution was added toa solution of 134.0 mg (233.1 μmol)3-(3′,3″-Dibenzyl-4″-(cyanomethoxy)-2-isobutyl-1,1′:4′,1″-terphenyl-4-yl)propanenitrile(29) in 8 ml MeOH, 8 ml THF and 1 ml 1,4-dioxane. The resulting mixturewas refluxed for 29 h and then cooled to 0° C. After adjusting the pH to2 by adding 1 N aq. HCl-solution, which led to a white precipitate,brine was added and the mixture was extracted with THF. The comb. org.fractions were washed twice with brine, dried over MgSO₄ and evaporated.Column chromatography (first CH₂Cl₂/MeOH (10+1), then EtOAc/HOAc (95+5))yielded 16.2 mg (26.4 μmol, 11%) 1b as a white solid: R_(f) (CH₂Cl₂/MeOH(10+1)) 0.20; ¹H NMR (500 MHz, d₄-MeOH+d₄-HOAc) δ1.06 (d, 6H, J=6.62Hz), 1.99 (m, 1H), 2.83 (d, 2H, J=7.25 Hz), 3.03 (t, 2H, J=7.57 Hz),3.31 (t, 2H, J=7.57 Hz), 4.31 (s, 2H), 4.40 (s, 2H), 5.09 (s, 2H), 7.27(m, 3H), 7.41 (d, 1H, J=2.21 Hz), 7.45-7.54 (m, 10H), 7.57-7.62 (m, 5H);¹³C NMR (100 MHz, d₄-MeOH+d₄-HOAc) δ20.86, 22.84, 30.58, 31.59, 31.61,36.67, 39.95, 43.23, 92.03, 112.62, 126.74, 126.80, 126.87, 128.35,129.28, 129.31, 129.32, 129.74, 130.13, 131.04, 131.14, 131.18, 131.39,132.69, 135.83, 139.17, 140.21, 140.77, 141.26, 141.47, 142.30, 142.38,142.94, 176.09, 176.14; LRMS (FAB) m/z 658 (16), 635 (19), 331 (16), 329(38), 309 (15), 297 (13), 193 (10), 179 (14), 177 (100), 155 (48), 154(14), 153 (26), 152 (23), 135 (52), 121 (18), 119 (100); HRMS (FAB)Calcd. for C₄₁H₄₀O₅Na: 635.277345. Found: 635.277200.

[0150] Lyophilization of 1b from NH₄OH led to the correspondingBisammonia salt:

[0151]¹H NMR (500 MHz, d₄-MeOH) δ0.67 (d, 6H, J=6.62 Hz), 1.59 (m, 1H),2.41 (d, 2H, J=7.41 Hz), 2.46 (t, 2H, J=8.04 Hz), 2.90 (t, 2H, J=8.20Hz), 3.90 (s, 2H), 4.05 (s, 2H), 4.43 (s, 2H), 6.85-6.91 (m, 3H), 6.94(d, 1H, J=1.89 Hz), 7.02-7.24 (m, 15H).

[0152] Synthesis Following the Presentation in FIGS. 5A, Scheme 5A and5B, Scheme 5B

3-Benzyl-phenol (31)

[0153] To a solution of m-hydroxybenzaldehyde 30 (5 g, 0.04 mol, 20 mlTHF, 0° C.) was added phenylmagnesium bromide (32.8 ml, 3 M in THF,0.010 mol). The reaction was stirred at 0° C. for one hour and thenrefluxed an additional hour. The solvent was removed by evaporation andthe residue was dissolved in ether, extracted with 1 M HCl, washed withbrine, and dried (MgSO₄). 69 (crude): ¹H NMR (500 MHz, CD₃OD) δ9.25 (s,1 H), 7.37-7.33 (m, 2H), 7.30-7.29 (m, 1 H), 7.20-7.18 (m, 1 H),7.08-7.05 (m, 1H), 6.78-6.77 (m, 12 H), 6.58-6.55 (m, 1H), 5.78 (d,J=4.0 Hz), 5.59 (d, J=4.0 Hz). The crude benzyl alcohol, 30(a), wasdissolved in methanol (20 ml) and hydrogenated (60 psi, 0.500 g Pd/C)for 5 hours. The reaction mixture was filtered through Celite andconcentrated to yield the substituted phenol which was purified bycolumn chromatography. (6.9 g, 0.038 mol, 93%).

[0154]¹H NMR (500 MHz, CDCl₃) δ7.30-7.27(m, 2 H), 7.21-7.13 (m, 4 H),6.78-6.77 (m, 1 H), 6.67-6.65 (m, 1 H), 6.63 (s, 1 H), 3.93 (s, 2 H),¹³C NMR (500 MHz, CDCl₃) δ155.3, 142.8, 140.7, 129.5, 128.8, 128.3,125.9, 121.3, 115.8, 113.0, 41.5.

3-Benzyloxy-benzaldehyde (32)

[0155] To a solution of 3-hydroxylbenzaldehyde 31 (5.0 g, 40 mmol) andK₂CO₃ (27.2 g, 197 mmol) in 200 ml CHCl₃: 100 ml MeOH was addedbenzylbromide (5.9 ml, 49 mmol). The suspension was refluxed undernitrogen overnight. The solvent was removed by evaporation and theresulting oil was taken up in DCM and washed with water and brine anddried (Na₂SO₄). The crude product was purified by column chromatographyto yield the product as a viscous oil which solidified upon sitting(8.48 g, 40 mmol, 98%). m.p. 46°. ¹H NMR (500 MHz, CDCl₃) δ9.97 (s, 1H), 7.48-7.25 (m, 9 H), 5.13 (s, 2 H). ¹³C NMR (125 MHz, CD₃OD) δ191.8,159.2, 137.8, 136.3, 130.0, 128.6, 128.1, 127.5, 123.41, 121.9, 113.3,70.0. HRMS (EI) m/e calcd for C₁₄H₁₂O₂: 212.08373, found: 212.0827.

[0156] General Condensation of Napthyllithium Derivatives with 32

[0157] To a solution of bromonaphthalene (6.0 mmol) in THF (10 ml, −78°)was added t-BuLi (12.5 mmol, 1.7 M in hexanes) dropwise. This solutionwas added slowly to a solution of 32 (7.1 mmol) in THF (5 ml, −78°) andthe mixture was allowed to warm to room temperature under nitrogen. Thereaction was quenched with dilute HCl and the product was extracted intoDCM, washed with acid and brine, dried (Na₂SO₄), and purified by columnchromatography.

(3-Benzyloxy-phenyl)-naphthalen-1-yl-methanol (33)

[0158]¹H NMR (500 MHz, CDCl₃) δ8.05 (d, J=7.1 Hz, 1 H), 7.86 (d, J=9.4Hz, 1 H), 7.83 (d, J=8.1 Hz, 1 H), 7.63 (d, J=7.1 Hz, 1 H), 7.50-7.23(m, 8 H), 7.07 (s, 1 H), 7.01 (d, J=7.6 Hz, 1 H), 6.89 (dd, J=8.0, 2.0Hz, 1 H), 6.52 (d, J=3.5 Hz, 1 H), 5.01 (s, 2H), 2.31 (d, J=4.0 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ159.0, 144.9, 138.7, 136.7, 134.0, 130.7,129.6, 128.8, 128.6, 128.55, 128.0, 127.6, 126.2, 125.6, 125.3, 124.7,124.0, 119.7, 114.0, 113.7. HRMS (EI) m/e calcd for C₂₄H₁₀O₂: 340.1463,found: 340.1459.

(3-Benzyloxy-phenyl)-naphthalen-2-yl-methanol (33)

[0159]¹H NMR (500 MHz, CDCl₃) δ7.84-7.77 (m, 3 H), 7.48-7.25 (m, 9 H),7.48-7.23 (m, 10 H), 7.07 (s, 1 H), 7.01 (d, J=10.0 Hz, 1 H), 6.49 (dd,J=10.0, 3.8), 5.97 (d, J=3.8 Hz, 1 H), 5.02 (s, 2 H). ¹³C NMR (125 MHz,CDCl₃) δ159.6, 144.8, 138.6, 136.7, 133.7, 130.6, 129.3, 128.5, 128.3,128.2, 127.7, 127.4,125.9, 125.4, 125.2, 124.5, 123.9, 119.6, 113.6,113.6,73.0, 69.6.

[0160] General Hydrogenation of Naphthylmethanol Derivatives

[0161] The naphthylmethanol derivatives 33 (6 mmol) were hydrogenated (1atm) in THF (10 ml) with HCl (1 ml) in the presence of Pd/C (100 mg) atatmospheric pressure of hydrogen. The suspension was stirred for 5 hrs,and then filtered through celite and concentrated in vacuo. The producteluted on TLC with the same R_(f) as the starting material, however theproduct stained pink with vanillin while the starting material stainedgrey. Separation from unreacted starting material was possible onlyafter the subsequent triflation.

3-Naphthalen-1-ylmethyl-phenol (33c)

[0162]¹H NMR (500 MHz, CDCl₃) δ7.90 (d, J=7.6 Hz, 1 H), 7.76 (d, J=7.1Hz, 1 H), 7.79 (d, J=8.3 Hz, 1 H), 7.40-7.31 (m, 3 H), 7.21 (d, J=6.8Hz, 1 H), 7.03 (t, J=7.8 Hz, 1 H), 6.72 (d, J=7.6 Hz, 1 H), 6.52 (m, 2H), 5.30 (bs, 1 H), 4.28 (s, 2 H). ¹³C NMR (125 MHz, CDCl₃) δ155.6,142.7, 136.2, 133.9, 132.1, 129.6, 128.7, 127.7, 127.3, 126.0, 125.5,125.6, 124.3, 121.3, 115.6, 113.0. HRMS (EI) m/e calcd for C₁₇H₁₄O:234.1045, found: 234.1046.

3-Naphthalen-2-ylmethyl-phenol (33c)

[0163]¹H NMR (500 MHz, CDCl₃) δ7.76-7.69 (m, 3 H), 7.57 (s, 1 H),7.41-7.38 (m, 2 H), 7.25 (d, J=8.6 Hz, 1 H), 7.09 (t, J=7.6 Hz, 1 H),6.77 (d, J=7.6 Hz, 1 H), 6.59 (m, 1 H), 5.16 (bs, 1 H), 4.00 (S, 2 H).

[0164] General Nitrosation

[0165] To a solution of 95% ethanol and HCl (90 ml, 1:1) was addedm-alkylphenol 40, 42 (0.074 mol). The solution was chilled (0° C.) andsodium nitrite (0.110 mol was added slowly as a neat solid. Thesuspension was stirred an additional 2 hours. The reaction was quenchedwith water, and the crude product was isolated by filtration. Theresulting solid was recrystalized from benzene.

3-Ethyl-4-nitroso-phenol (41)

[0166] m.p. 134°. ¹H NMR (500 MHz, CDCl₃) δ9.15 (s, 1 H), 7.79 (d, J=10Hz, 1 H), 6.44 (d, J=10.5 Hz, 1 H), 6.35 (m, 1 H), 2.64 (q, J=7.5 Hz, 2H), 1.20 (t, J=7.5 Hz, 2 H). ¹³C NMR (125 MHz, CD₃OD) δ189.7, 155.7,150.8, 130.9, 127.2, 126.5, 25.2, 14.5; HRMS (EI) m/e calcd for C₈H₉NO₂:151.0633, found: 151.0635.

3-Isopropyl-4-nitroso-phenol (42)

[0167] m.p. 153°. ¹H NMR (500 MHz, CD₃OD) δ7.71 (d, J=10 Hz, 1 H), 6.26(d, J=10 Hz, 1 H), 6.21 (s,1 H), 3.26 (m, 1 H), 1.12 (d, J=6.5 Hz, 6 H).¹³C NMR (125 MHz, CD₃OD) δ189.7, 159.7, 150.1, 130.1, 126.5, 125.0,28.8, 23.3.

[0168] General Hydrogenation of Nitro and Nitroso Phenols

[0169] The nitro- or nitroso-phenol (28.7 mmol) was dissolved in acidicmethanol or THF (50 ml methanol, 2 ml HCl) and Pd/C (0.300 g) was added.The reaction was hydrogenated (60 psi for MeOH and atmospheric pressurefor THF) overnight. The catalyst was removed by Celite filtration andthe solvent was removed by evaporation. The crude anilinium derivativewas neutralized (extraction with EtOAc from NaOH) and purified by columnchromatography but, because the product was highly susceptable tooxidation (as exhibited by dark color formation) it was generally usedimmediately as crude material.

4-Hydroxy-2-methyl-phenyl-ammonium chloride (41d)

[0170]¹H NMR (300 MHz, DMSO-d6) δ9.97 (bs, 3 H), 9.71 (bs, 1 H), 7.23(d, 1 H), 6.72 (m, 1 H), 6.57 (dd, 1H).

2-Ethyl-4-hydroxyl-phenyl-ammonium chloride (43d)

[0171]¹H NMR (300 MHz, DMSO-d6) δ8.33(bs, 1 H), 6.33-6.20 (m, 3 H), 4.23(bs, 2 H), 2.51 (q, J=5.7 Hz,2 H), 0.97 (t, J=5.4 Hz 3H).

[0172] General Sandmeyer Reaction

[0173] The anilinium salts (27.8 mmol) from the nitroso/nitrohydrogenations were dissolved in cold water (50 ml) with enough methanolto provide solubility. The solution was cooled (0° C.) and sulfuric acid(31.5 mmol) was added. An aqueous solution of sodium nitrite (36.1 mmol,in 5 ml water) was added over the course of one hour. The reaction wasstirred for another hour at 0° C. upon which time another aliquot ofcold sulfuric acid (0.5 ml) was added. A solution of potassium iodide(51.6 mmol) in water and copper bronze (2.3 mmol) were added. After aone hour reflux, the mixture was cooled and extracted with DCM andsubsequently washed with sodium thiosulfate (1M), brine, and dried(Na₂SO₄). The resutling orange oil was difficult to purify by columnchromatography and was therefore usually used crude in the silylation.

3-Ethyl-4-iodo-phenol (41e)

[0174]¹H NMR (300 MHz, DMSO-d6) δ7.63 (d, J=8.4, 1 H), 6.75 (d, J=2.9,1H), 6.44 (dd, J=2.9, 8.4), 4.70 (bs, 1 H), 2.67 (q, J=7.8, 2H), 1.19(t, J=7.7, 3H).

[0175] General Silylation

[0176] The concentrated iodophenois (28.7 mmol) were dissolved in DMF(20 ml) and imidazole (71.7 mmol) and t-butyldimethylsilylchloride (34.4mmol) were added. The reaction was stirred overnight after which timethe reaction was diluted with water and extracted with hexanes. Theorganic layers were washed with brine and dried (Na₂SO₄). The resultingoil was purified via silica gel column chromatography (hexanes), toyield the silyl ethers as a colorless oils.

tert-Butyl-(4-iodo-3-methyl-phenoxy)-dimethyl-silane

[0177]¹H NMR (500 MHz, CDCl₃) δ7.59 (d, J=8.5 Hz, 1 H), 6.75 (d, J=2.2Hz, 1 H), 6.41 (dd, J=2.9, 8.5 Hz, 1 H), 2.36 (s, 3 H), 0.97 (s, 9 H),0.18 (s, 6 H).

tert-Butyl-(3-ethyl-4-iodo-phenoxy)-dimethyl-silane (41f)

[0178]¹H NMR (500 MHz, CDCl₃) δ7.61 (d, J=8.5 Hz, 1 H), 6.73 (d, J=3 Hz,1 H), 6.41 (dd, J=3, 8.5 Hz, 1 H), 2.65 (q, J=8, 2 H), 1.18 (t, J=7.5Hz, 3 H), 0.98 (s, ˜9 H), 0.19 (s, 6 H). ¹³C NMR (125 MHz, CD₃OD)δ156.2, 147.6, 139.7, 120.7, 119.7, 89.9, 34.1, 25.7, 18.2, 14.5, −4.4;HRMS (EI) m/e calcd for C₁₄H₂₃OSiI: 362.0563, found: 362.0564.

tert-Butyl-(4-iodo-3-isopropyl-phenoxy)-dimethyl-silane (43f)

[0179]¹H NMR (500 MHz, CDCl₃) δ7.63 (d, J=8.5 Hz, 1 H), 6.75 (d, J=3 Hz,1 H), 6.44 (dd, J=2.5, 8.5 Hz, 1 H), 3.10 (sept, J=6.5 Hz, 1 H), 1.22(d, J=7.0 Hz, 6 H), 0.91 (s, 9 H), 0.21 (s, 6 H); HRMS (EI) m/e calcdfor C₁₅H₂₅OSiI: 376.0719, found: 376.0719.

[0180] General Triflation

[0181] To a solution of phenol (2.3 mmol) in dry DCM (50 ml, 0° C.) wasadded DIEA (2.7 mmol) and Tf₂O (2.7 mmol) were added slowly. Thesolution was stirred for 1 hour. The reaction was diluted with DCM andwashed with cold water and brine and dried (Na₂SO₄). The resulting crudeoil was purified by column chromatography.

Trifluoro-methanesulfonic acid 3-methyl-4-nitro-phenyl ester

[0182]¹H NMR (300 MHz, CDCl₃) δ8.10 (m, 1 H), 7.33 (m, 2 H), 2.66 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ151.6, 148.6, 137.2, 127.2, 125.6, 120.1,118.9 (q, J=319 Hz), 20.5. LRMS (EI) m/e calcd for C8H3NO₅SF₃: 285.0,found: 285.0.

Trifluoro-methane sulfonic acid 3-benzyl-phenyl ester (45)

[0183]¹H NMR (300 MHz, CDCl₃) δ7.60-7.20 (m, 9 H), 4.1 (s, 2 H). ¹³C NMR(300 MHz, CDCl₃) δ153.0, 145.1, 139.8, 132.3, 128.2, 127.5, 126.1,123.2, 122.0, 119.6, 117.0,42.3. ¹³C NMR (125 MHz, CDCl₃) δ149.4, 144.4,139.7, 130.3, 129.0, 128.9, 126.8, 121.8, 119.0, 119.2 (q, J=321 Hz)118.3, 41.6. 0.6. HRMS (EI) m/e calcd for C₁₄H₉O₃SF₃: 315.0235, found:315.0303.

Trifluoro-methane sulfonic acid 3-naphthalene-1-ylmethyl-phenyl ester(35d-1)

[0184]¹H NMR (300 MHz, CDCl₃) δ7.89 (d, J=6.9 Hz, 2 H), 7.81 (d, J=8.2Hz, 1 H), 7.46 (m, 3 H), 7.34-7.28 (m, 2 H), 7.19 (d, J=7.9 Hz, 1 H)7.11 (m, 2 H), 4.49 (s, 2 H). ¹³C NMR (125 MHz, CDCl₃) δ149.8, 143.8,135.1, 134.0, 131.8, 130.2, 128.8, 128.7, 127.7, 127.5, 126.3, 125.8,125.6, 123.9, 121.5, 121.2 (q, J=320 Hz),119.0, 38.7. HRMS (EI) m/ecalcd for C₁₈H₁₃O₃SF₃: 366.0537, found: 366.0539.

Trifluoro-methane sulfonic acid 3-naphthalene-2-ylmethyl-phenyl ester(35d-2)

[0185]¹H NMR (300 MHz, CDCl₃) δ7.78 (m, 3 H), 7.62 (s, 1 H), 7.46 (m, 2H), 7.36 (t, J=7.9, 1 H), 7.28-7.24 (m, ˜4 H), 7.14 (m, 2 H). ¹³C NMR(125 MHz, CDCl₃) δ149.8, 144.1, 137.0, 133.6, 132.3, 130.2, 129.0,128.5, 127.6, 127.7, 127.3, 127.2, 126.3, 125.7, 121.9 (q, J=320 Hz,),121.8, 119.1. HRMS (EI) m/e calcd for C₁₈H₁₃O₃SF₃: 366.0537, found:366.0539.

Trifluoro-methane sulfonic acid 2,3′-dimethyl-4′-nitro-biphenyl-4-ylester

[0186]¹H NMR (300 MHz, CDCl₃) δ8.08 (m, 2H), 7.30-7.17 (m, 5 H), 2.67(s, 3 H), 2.31 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ149.1, 148.3, 145.1,140.0, 138.2, 134.0, 133.4, 131.1, 127.6, 124.9, 123.1, 118.9, 118.7 (q,J=387.7), 20.7, 20.6. HRMS (EI) m/e calcd for C₂₇H₁₂NO₅SF₃: 376.0467,found: 376.0467.

Trifluoro-methane sulfonic acid2-ethyl-3′-naphthalen-1-lymethyl-biphenyl-4-yl ester (49-d1)

[0187]¹H NMR (300 MHz, CDCl₃) δ7.98 (m, 1 H), 7.87 (m, 1 H), 7.77 (m,1H) 7.44 (m, 3 H), 7.32 (m, 2 H), 7.25 (m, 1 H), 7.19 (m, 1 H), 7.08 (m,4 H), 4.49 (s, 2 H), 2.44 (q, J=8.0 Hz, 2 H), 0.94 (t, H=8.0 Hz, 3 H).HRMS (EI) m/e calcd for C₂₈H₁₈O₃SF₃: 470.1164, found: 470.1163.

Trifluoro-methane sulfonic acid2-ethyl-3′-naphthalen-2-lymethyl-biphenyl-4-yl ester (49-d2)

[0188]¹H NMR (300 MHz, CDCl₃) δ7.74 (m, 2 H), 7.61 (s, 1 H), 7.39 (m, 2H), 7.30 (m, 2 H), 7.23-7.04 (m, 7 H), 4.13 (s, 2 H), 2.53 (q, J=7.3 Hz,2 H), 1.02 (t, J=7.5 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃) δ148.9, 144.5,141.9, 141.1, 140.3, 138.3, 133.6, 132.1, 131.5, 129.7, 128.4, 128.2,128.1, 127.5, 127.2, 126.9, 126.1, 125.5, 124.3, 121.0, 119.7 (q, J=327)118.2, 42.1, 26.3, 15.1. HRMS (EI) m/e calcd for C₂₈H₁₈O₃SF₃: 470.1164,found: 470.1163.

[0189] General Aryl-Aryl Coupling

[0190] Following the general method of Baston and Hartmann, Synth.,Commun., 28, 2725-2729 (1998) and Mislow, et al., J. Am. Chem. Soc., 84,1455-1478 (1962). To a solution of the iodo-silylethers (3.00 mmol) inTHF (30 ml, −78° C.) t-butyllithium (1.5 M in hexanes, 5.96 mmol) wasadded dropwise. The solution was stirred 15 min, freshly fused zincchloride (3.57 mmol) was added and the reaction was stirred at 0° C. foran additional 30 min. This was then added to a solution of triflate(2.83 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.298 mmol) and1,1′-bis(diphenylphosphino)-ferrocene (0.298 mmol) in THF (5 ml). Thereaction was refluxed under nitrogen overnight. The solution was dilutedwith 0.5 M HCl and extracted with ethyl acetate. The combined organiclayers were washed with brine and dried (Na₂SO₄). The crude product wasfiltered through a plug of silica gel (this was necessary to ensure thatall the palladium was removed, otherwise desilylation on silica gel issometimes observed) and then purified by means of column chromatography.It was found that the difficulty of separation of the very non-polarproduct from unreacted iodide or triflate could be overcome by firstsubjecting the material to deprotecting conditions.

tert-Butyl-(2,3′-dimethyl-4′-nitro-biphenyl-4-yloxy)-dimethyl-silane

[0191]¹H NMR (300 MHz, CDCl₃) δ8.02 (d, J=8.9, 1 H), 7.28 (m, ˜2 H),7.06 (d, J=8.1 Hz, 1 H), 6.77 (m, 1 H), 6.73 (m, 1 H), 2.66 (s, 3 H),2.23 (s, 3 H), 1.01 (s, 9 H), 0.24 (s, 6 H). ¹³C NMR (125 MHz, CDCl₃)δ155.7, 147.4, 147.2, 136.5, 133.70, 133.65, 132.8, 130.5, 127.9, 124.7,122.1, 117.6, 25.7, 20.9, 20. 7, 18.2, −4.4. HRMS (EI) m/e calcd forC₂₀H₂₇NO₃Si: 357.1760, found: 357.1758.

tert-Butyl-dimethyl-(3,2,2,-trimethyl-4-nitro-[1,1′,4′,1″]terphenyl-4″-yloxy)-silane

[0192]¹H NMR (300 MHz, CDCl₃) δ8.06 (d, J=8.0 Hz, 1 H), 7.35 (m, 2 H),7.21 (m, 3 H), 7.11 (d, J=8.0 Hz, 1 H), 6.77 (d, J=4.0 Hz, 1 H), 6.73(dd, J=8.0, 4.0 Hz, 1 H), 2.67 (s, 3 H), 2.31 (s, 3 H), 2.28 (s, 3 H),1.01 (s, 9 H), 0.24 (s, 6 H).). ¹³C NMR (125 MHz, CDCl₃) δ154.9, 147.7,147.1, 141.9, 137.7, 163.5, 134.7, 134.4, 133.6, 133.5, 131.7, 130.7,129.1, 127.8, 127.1, 124.7, 121.8, 117.3, 25.7, 20.74, 20.65, 20.4,18.2, −4.4. HRMS (EI) m/e calcd for C₂₇H₃₃NO₃Si: 447.2230, found:447.2230.

(3′-Benzyl-2-ethyl-biphenyl-4-yloxy)-tert-butyl-dimethyl-silane (47)

[0193]¹H NMR (300 MHz, CDCl₃) δ7.33-7.29 (m, 3 H), 7.24-7.22 (m, 3 H),7.17-7.14 (m, 3 H), 7.05 (d, J=8.1 Hz, 1 H), 6.77 (s, 1 H), 6.70 (d,J=8.1, 1 H) 4.03 (s, 2 H), 2.51 (q, J=7.7, 2 H), 1.07 (t, J=7.4, 3 H),1.02 (s, 9 H), 0.25 (s, 6 H). ¹³C NMR (125 MHz, CDCl₃) δ154.9, 142.9,142.0, 141.2, 140.8, 134.8, 130.8, 130.2, 129.0, 128.5, 128.1, 127.2,127.0, 126.1, 119.9, 117.0, 42.0, 26.2, 25.8, 18.3, 15.6, −4.3. HRMS(EI) m/e calcd for C₂₇H₃₄SiO: 403.2456, found: 403.2457.

(3-Benzyl-2′-ethyl-2″-isopropyl-[1,1′,4′,1″]terphenyl-4″yloxy)-tert-butyl-dimethyl-silane(48)

[0194]¹H NMR (300 MHz, CDCl₃) δ7.35-7.28 (m, 3 H), 7.23-7.18 (m, 8 H),7.11 (m, 1 H), 7.08 (d, J=8.0 Hz, 1 H), 6.84 (d, J=4.0 Hz, 1 H), 6.70(dd, J=8.0, 4.0 Hz, 1 H), 4.04, (s, 2 H), 3.09, (sept, J=4.0 Hz, 1 H),2.60 (q, J=8.0 Hz, 2 H), 1.17 (d, J=4.0 Hz, 6 H), 1.09 (t, J=8.0 Hz, 3H), 1.02 (s, 9 H), 0.25 (s, 6 H). HRMS (EI) m/e calcd for C₃₆H₄₄SiO:520.3130 found: 520.3161.

tert-Butyl-(2′-ethyl-2″isopropyl-3-naphthalen-1-ylmethyl-[1,1′,4′,1″]terphenyl-4″-yloxy)-dimethyl-silane(51-1)

[0195]¹H NMR (300 MHz, CDCl₃) δ8.02 (d, J=6.9, 1 H), 7.85 (d, J=6.8 Hz,1 H), 7.76 (d, J=8.2 Hz, 1 H), 7.47-7.40 (m, 4 H), 7.33-7.28 (m, 2 H),7.16 (d, J=7.6 Hz, 1 H), 7.10 (s, 1 H), 7.02 (d, J=8.2 Hz, 1 H), 6.71(d, J=2.6 Hz, 1 H), 6.65 (dd, J=8.2, 2.5 Hz, 1 H), 4.48 (s, 2 H), 2.39(sept, J=7.6 Hz, 1 H), 1.01 (s, 9H), 0.95 (t, J=7.8, 3 H), 0.24 (s, 6H). ¹³C NMR (125 MHz, CDCl₃) δ154.9, 142.9, 141.9, 140.3, 136.7, 134.7,134.0, 132.2, 130.8, 129.9, 128.7, 128.1, 127.4, 127.26, 127.24, 126.9,125.9, 125.56, 125.55, 124.4, 119.9, 117.0, 39.2, 29.7, 26.2, 18.2,15.5, −4.3. HRMS (EI) m/e calcd for C₄₀H₄₆OSi: 570.3318, found:570.3318.

tert-Butyl-(2′-ethyl-2″isopropyl-3-naphthalen-2-ylmethyl-[1,1′,4′,1″]terphenyl-4″-yloxy)-dimethyl-silane(51-2)

[0196]¹H NMR (300 MHz, CDCl₃) δ7.82 (m, 4 H), 7.67 (s, 1 H), 7.44 (m, 3H), 7.35 (m, 2 H), 7.24-7.18 (m, 3 H), 7.11-7.06 (m, 2 H), 6.83 (d,J=2.5 Hz, 1 H), 6.69 (dd, J=8.3, 2.5, 1 H), 4.21 (s, 2 H), 3.08 (sept,J=8.0 Hz, 1 H), 2.60 (q, J=7.6, 2 H), 1.16 (d, J=6.8, 6 H), 1.07 (t,J=7.6 Hz 3 H), 1.01 (s, 9 H), 0.24 (s, 6 H).). ¹³C NMR (125 MHz, CDCl₃)δ155.1, 147.8,142.0, 141.0, 140.7, 139.7, 138.7, 134.1, 133.6, 132.1,130.9, 130.1, 129.8, 129.5, 128.2, 128.1, 127.7, 127,63, 127.55, 127.4,127.19, 127.15, 126.7, 126.0, 125.4, 116.99, 116.97, 42.16, 29.73,29.69, 25.8, 24.4, 18.3, 15.7, −4.3. HRMS (EI) m/e calcd for C₄₀H₄₇OSi:570.3345 found: 570.3318.

[0197] General Desilylation

[0198] The silyl ethers (2.0 mmol) were dissolved in dry THF (20 ml, 0°C.) and TBAF (4.0 mmol, 1 M in THF) was added dropwise and the reactionwas stirred at 0° C. for 0.5 hr, after which time the solution wasdiluted with 1M HCl and extracted into DCM. The organic layers werewashed with brine and dried (Na₂SO₄) and the resulting crude oil waspurified by column chromatography.

2,3′-Dimethyl-4′-nitro-biphenyl-4-ol

[0199]¹H NMR (300 MHz, CDCl₃) δ8.04 (d, J=8.8, 1 H), 7.26 (m, 2 H), 7.10(d, J=8.3, 1 H), 6,76, (m, 2 H), 5.06 (bs, 3 H), 2.66 (s, 3 H), 2.24 (s,3 H).

3,2′,2″,2′″-Tetramethyl-4-nitro-[1,1′,4′,1″,4″,1′″]quaterphenyl-4′″-ol

[0200]¹H (300 MHz, CDCl₃) δ8.04 (d, J=8.8 Hz, 1 H), 7.38 (m, 2 H),7.32-7.25 (m, 4 H), 7.22-7.15 (m, 3 H), 6.78-6.74 (m, 2 H), 2.69 (s, 3H), 2.37 (s, 3 H), 2.34 (s, 3 H), 2.31 (s, 3 H). ¹³C NMR (125 MHz,CDCl₃) δ154.7, 147.8, 147.1, 141.9, 140.7, 139.4, 138,1, 137.1, 134.93,134.85, 134.4, 133.7, 133.6, 131.6, 131.5, 131.1, 129.4, 129.2, 127.8,127.0, 126.9, 124.7, 117.0, 112.7, 20.8, 20.7, 20.6, 20.5.

3′-Benzyl-2-ethyl-biphenyl-4-ol (47j)

[0201]¹H NMR (500 MHz, CDCl₃) δ7.30-7.24 (m, 3 H), 7.20-7.09 (m, 6 H),7.05 (d, J=8 Hz), 6.75 (d, J=3 Hz, 1 H), 6.65 (m, 1 H) 5.2 (bs, 1 H),3.99 (s, 2 H), 2.49 (q, J=7.5 Hz, 2 H), 1.02 (t, J=7 Hz, 3 H). ¹³C NMR(125 MHz, CDCl₃) δ154.8, 143.4, 141.7, 141.1, 140.8, 134.5, 131.2,130.1, 129.0, 128.5, 128.1, 127.2, 127.1, 126.1, 115.2, 112.5, 42.0, 26,2, 15.4. HRMS (EI) m/e calcd for C₂₁H₁₈O: 286.1514 found: 286.1511.

3-Benzyl-2′-ethyl-2″-isopropyl-[1,1′,4′,1″]terphenyl-4″-ol (48j)

[0202]¹H NMR (500 MHz, CDCl₃) δ7.35-7.28 (m, 3 H), 7.25-7.18 (m, 8 H),7.11 (d, J=8.1 Hz 1 H), 6.85 (d, J=2.6, 1 H), 6.70 (dd, J=8.1, 2.6 Hz, 1H), 4.74 (bs, 1 H), 4.04 (s, 2 H), 3.11 (sept, J=6.6, 1 H), 2.60 (q,J=7.4, 2 H), 1.18 (d, J=7.0, 6 H), 1.08 (t, J=7.7, 3 H). ¹³C NMR (125MHz, CDCl₃) δ153.0, 148.4, 142.0, 141.13, 141.11, 140.9, 140.8, 139.8,134.0, 131,3, 130.0, 129.8, 129.6, 129.0, 128.5, 128.2, 127.4, 127.1,126.7, 126.1,112.4, 112.3, 42.0, 29.7, 26.2, 24.4, 15.7. HRMS (EI) m/ecalcd for C₃₀H₂₉O: 406.2297 found: 406.2295.

2-Ethyl-3′-naphthalen-1-ylmethyl-biphenyl-4-ol (51f-1)

[0203]¹H NMR (500 MHz, CDCl₃) δ8.00 (m, 1 H), 7.85 (m, 1 H), 7.75 (d,J=8.1 Hz, 1 H), 7.42 (m, 3 H), 7.28 (m, 2 H), 7.18 (m, 1 H), 7.08 (m, 2H), 7.02 (d, J=8.1 Hz, 1 H), 6.69-6.63 (m, 2 H).

2-Ethyl-3′-naphthalen-2-ylmethyl-biphenyl-4-ol (51f-2)

[0204]¹H NMR (500 MHz, CDCl₃) δ7.80 (m, 3H), 7.66 (s, 1 H), 7.43 (m, 2H), 7.35 (m, 2 H), 7.24-7.18 (m, 5 H), 7.08 (m, 2 H), 6.84 (s, 1 H),6.67 (d, J=7.0, 1 H), 5.31 (bs, 1 H), 4.18 (s, 2 H), 3.10 (sept, J=6.9Hz, 1 H), 2.60 (q, J=7.8 Hz, 2 H), 1.15 (d, J=7.0 Hz, 6 H), 1.06 (t,J=7.6 Hz, 3 H).

[0205] General Etherification with Benzyl Bromoacetate.

[0206] The phenol (1.6 mmol) was dissolved in DMF (5 ml) with K₂CO₃ (4.9mmol) and heated to 70° C., and benzyl bromo acetate (4.2 mmol) wasadded. The reaction was heated for 1 hour after which time the solutionwas diluted with water and extracted with DCM. The combined organiclayers were washed with brine and dried (Na₂ SO₄), and the concentratedproduct was purified by silica gel chromatography.

(3-Benzyl-2′-ethyl-2″-isopropyl-[1,1′,4′,1″]terphenyl-4″-yloxy)-aceticacid benzyl ester (48l)

[0207]¹H NMR (500 MHz, CDCl₃) δ7.38-7.16 (m, ˜17 H), 7.98 (m, 1 H), 6.73(m, 1 H), 4.68 (s, 2 H), 4.03 (s, 2 H), 3.84 (s, ˜2 H), 3.12 (sept,J=7.0 Hz, 1 H), 2.58 (q, J=7.0 Hz, 2 H), 1.17 (d, J=7.5 Hz, 6 H), 1.08(t, J=7.0 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃) δ172.5, 169.0, 161.3,157.3, 148.3, 141.9, 141.1, 140.9, 140.6, 139.9, 131.1, 130.0, 129.8,129.6, 129.0, 128.7, 128.6, 128.5, 128.2, 127.4, 127.1, 126.3, 126.1,112.5, 67.3, 65,5, 42.0, 29.7, 26.2, 24.3, 15.7.

(2′-Ethyl-2″-isopropyl-3-naphthalen-2-ylmethyl-[1,1′,4′,1″]terphenyl-4″-yloxy)-aceticacid benzyl ester (51h-2)

[0208]¹H NMR (500 MHz, CDCl₃) δ7.79 (m, 3 H), 7.67 (s, 1 H), 7.44 (m, 2H), 7.35 (m, 7 H), 7.29-7.03 (m, ˜9 H), 6.96 (d, J=4.0 Hz, 1 H), 6.73(dd J=8.0, 4.0 Hz, 1 H), 5.27 (s, 2 H), 4.71 (s, 2 H), 4.21 (s, 2 H),3.09 (sept, J=7.9 Hz, 1 H), 2.60 (q, J=8.0 Hz, 2 H), 1.17 (d, J=7.8 Hz,6 H), 1.07 (t, J=8.0 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃) δ169.0, 157.3,148.3, 141.8, 141.1, 140.6, 140.4, 140.4, 139.8, 136.6, 135.2, 134.9,134.0, 132.2, 131.0, 129.6, 129.7, 129.5, 128.69, 128.67, 128.60 128.56,128.50, 128.2, 127.5, 127.2, 127.2, 127.1, 126.6, 125.9, 125.6, 124.4,112.5, 110.9, 67.0, 65.5, 39.2, 29.7, 26.1, 24.3, 15.6. HRMS (EI) m/ecalcd for C₄₃H₄₀O₃: 604.2977 found: 604.2978.

[0209] Hydrolysis of Benzyl Esters

[0210] The ester (1.6 mmol) was dissolved in 5 ml 5%KOH in MeOH with asmall amount of DCM to aid in solubilization. The solution was stirredat room temperature for 30 min, after which time it was acidified andextracted into DCM. The combined organic layers were washed with acidicbrine and dried (Na₂SO₄). The product was passed through a plug ofsilica gel and then purified by reverse phase HPLC. The resultinglyophized product was taken up in distilled water and NH₄OH and thesolvent was lyophilzed to yield the ammonium salt.

(3-Benzyl-2′-ethyl-2″-isopropyl-[1,1′,4′,1″]terphenyl-4″-yloxy)-aceticacid (48m)

[0211]¹H NMR (500 MHz, CD₃OD) δ8.00 (bs, 1 H), 7.33 (m, 1 H), 7.28-7.05(m, 12 H), 6.95 (d, J=4.0 Hz, 1 H), 6.78 (dd, J=4.0, 8.0 Hz, 1 H), 4.68(s, 2 H), 4.01 (s, 2 H), 3.08 (sept, J=7.6 Hz, 1 H), 2.55 (q, J=8.1 Hz,2 H), 1.16 (d, J=7.8 Hz, 6 H), 1.01 (t, J=7.8 Hz, 3 H). HRMS (EI) m/ecalcd for C₃₀H₃₈O₃: 446.1494 found: 446.2821.

Ammonium(3-benzyl-2′-ethyl-2″-isopropyl-[1,1′,4′,1″]terphenyl-4″yloxy)-acetate(48.NH₄)

[0212]¹H NMR (500 MHz, CD₃OD) δ7.36 (m, 1 H), 7.29-7.15 (m, 10 H), 7.07(m, 2 H), 6.91 (s, 1 H), 6.72 (d, J=7.9 Hz, 1 H), 5.76 (bs, ˜2 H), 4.51(s, 2 H), 4.00 (s, 2 H), 2.91 (sept, 7.9 Hz, 1 H), 2.50 (q, J=8.2 Hz, 2H), 1.20 (d, J=7.5 Hz, 6 H), 0.92 (t, 7.9 Hz, 3 H). ¹³C NMR (125 MHz,CD₃OD) δ158.2, 147.4, 141.68, 141.65, 141.5, 140.9, 140.8, 139.6, 133.2,130.9, 129.9, 129.8, 129.1, 128.8, 128.7, 127.6, 127.0, 126.4, 112.3,111.5, 55.3, 48.9, 29.6, 25.9, 24.5, 14.0. HRMS (EI) m/e calcd forC₃₂H₃₅O₂N: 487.2273 found: 487.2268.

(2′-Ethyl-2″-isopropyl-3-naphthalen-1-ylmethyl-[1,1′,4′,1″]terphenyl-4″-yloxy)-aceticacid (51i-1)

[0213]¹H NMR (500 MHz, CD₃OD) δ8.03 (m, 1 H), 7.86 (m, 1 H), 7.77 (s,J=8.2 Hz, 1 H), 7.54 (m, 3 H), 7.33 (m, 2 H), 7.23-7.13 (m, 6 H), 7.07(m, 1 H), 6.99 (m, 1 H), 6.73 (m, 1 H), 4.72 (s, 2 H), 4.51 (s, 2 H),3.12 (sept, J=6.9 Hz, 1 H), 2.49 (q, J=7.6 Hz, 2 H), 1.17 (d, J=6.9, 6H), 0.97 (t, J=7.3 Hz, 3 H). ¹³C NMR (125 MHz, CD₃OD) δ173.9, 156.9,148.5, 141.8, 141.2, 140.44, 139.9, 136.6, 135.3, 134.0, 132.2, 129.79,129.72, 129.5, 128.7, 128.2, 127.4, 127.2, 127.2,127.1, 126.6, 125.9,125.6, 124.4, 112.6, 110.8, 65.0, 39.2, 29.7, 26.1, 24.3, 15.5. HRMS(EI) m/c calcd for C₃₆H₃₄O₃: 514.2508 found: 514.2509.

(2′-Ethyl-2″-isopropyl-3-naphthalen-2-ylmethyl-[1,1′,4′,1″]terphenyl-4″-yloxy)-aceticacid (51i-2)

[0214]¹H NMR (500 MHz, CD₃OD) δ7.77 (m, 3 H), 7.66 (s, 1 H), 7.43 (m, 2H), 7.35 (m, 2 H), 7.24-7.16 (m, 6 H), 7.09 (d, J=7.6, 1 H), 6.99 (s, 1H), 6.76 (d, J=8.2 Hz, 4.71 (s, 2 H), 4.19 (s, 2 H), 3.11 (sept, J=6.6Hz, 1 H), 2.60 (q, J=7.35 Hz, 2 H), 1.17 (d, J=6.9 Hz, 6 H), 1.06 (t,J=7.6 Hz, 3 H). ¹³C NMR (125 MHz, CD₃OD) δ157.0, 148.5, 141.9, 141.1,140.8, 140.5, 139.9, 138.6, 135.3, 133.6, 132.1, 131.2, 130.1, 129.7,129.6, 128.2, 128.1, 127.8, 127.7, 127.6, 127.5, 127.2, 126.6, 126.0,125.4, 112.6, 110.8, 65.1, 42.2, 29.6, 26.2, 24.3, 15.6. HRMS (EI) m/ecalcd for C₃₆H₃₄O₃: 514.2508 found: 514.2509.

[0215] Synthesis Following the Presentation in FIG. 6, Scheme 6

[0216] Synthesis of the benzyl-bisisobutyl-terphenyl Derivative 58.

3-(3′-Benzyl-2,3″-diisobutyl-4″-methoxy-1,1:4′,1″-terphenyl-4-yl)propanenitrile(55)

[0217] 134.6 mg (0.27 mmol) Trifluoro-methanesulfonic acid3-benzyl-4′-(2-Cyano-ethyl)-2′-isobutyl-biphenyl-4-yl ester (54), 96.9mg (0.33 mmol, 1.24 eq.)2-(3-isobutyl-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(11) and 46.7 mg (40 μmol, 0.15 eq.) Pd(Ph₃P)₄ were dissolved in 7 mlDME/EtOH (9+1). To this yellow solution 0.27 ml (0.54 mmol, 2.00 eq.) ofa 2 M aq. Na₂CO₃-solution was added and the resulting mixture was heatedat 80° C. for 19 h. After concentrating the mixture in vacuo the residuewas taken up in water and extracted with CH₂Cl₂. The comb. org.fractions were dried over MgSO₄ and evaporated. Column chromatography(hexanes/EtOAc (6+1)) yielded 122.9 mg (0.24 mmol, 88.26%)3-(3′-Benzyl-2,3″-diisobutyl-4″-methoxy-1,1′:4′,1″-terphenyl-4-yl)propanenitrile(55) as a clear oil. R_(f) (hexanes/EtOAc (6+1))=0.20. ¹H-NMR (500 MHz,CDCl₃): δ=0.69 (d, 6H, J=6.62 Hz, 2*CH₃), 0.84 (d, 6H, J=6.62 Hz,2*CH₃), 1.63 (m, 1H, CH), 1.83 (m, 1H, CH), 2.42 (d, 2H, J=7.25 Hz,CH₂), 2.44 (d, 2H, J=7.25 Hz, CH₂), 2.61 (t, 2H, J=7.41 Hz, CH₂CH₂CN),2.93 (t, 2H, J=7.41 Hz, CH₂CH₂CN), 3.81 (s, 3H, OCH₃), 3.98 (s, 2H,CH₂Ph), 6.81 (d, 1H, J=8.51 Hz), 6.96 (m, 2H), 7.00-7.18 (m, 10H),7.24-7.26 (d, 1H, J=7.57 Hz). MS (EI): m/z=517 (10), 516 (45), 515(100), 472 (10), 381 (8), 91 (20). HR-MS (EI): Calcd. for C₃₇H₄₁NO:515.318814. Found: 515.319235.

3-(3′-Benzyl-4″-hydroxy-2,3″-diisobutyl-1,1′:4′,1″-terphenyl-4-yl)propanenitrile(56)

[0218] 0.71 ml (0.71 mmol, 2.98 eq.) of a 1 M solution of BBr₃ in CH₂Cl₂was added to a solution of 122.8 mg (0.238 mmol)3-(3′-Benzyl-2,3″-diisobutyl-4″-methoxy-1,1′:4′,1″-terphenyl-4-yl)propanenitrile(55) in 5 ml dry CH₂Cl₂ at 0° C. via syringe. After that the solutionwas stirred for 90 min at 0° C. and then for 5 h at r.t. The reactionmixture was then added to water and extracted with CH₂Cl₂. The comb.org. fractions were dried over MgSO₄ and evaporated. Columnchromatography (hexanes/EtOAc (2+1)) yielded 119.3 mg (0.24 mmol,99.91%)3-(3′-Benzyl-4″-hydroxy-2,3″-disobutyl-1,1′:4′,1″-terphenyl-4-yl)propanenitrile(56) as a colorless oil. R_(f) (hexanes/EtOAc (2+1))=0.40. ¹H-NMR (500MHz, CDCl₃): δ=0.69 (d, 6H, J=6.62 Hz, 2*CH₃), 0.86 (d, 6H, J=6.62 Hz,2*CH₃), 1.63 (m, 1H, CH), 1.87 (m, 1H, CH), 2.43 (d, 2H, J=7.25 Hz,CH₂), 2.47 (d, 2H, J=7.09 Hz, CH₂), 2.61 (t, 2H, J=7.41 Hz, CH₂CH₂CN),2.93 (t, 2H, J=7.41 Hz, CH₂CH₂CN), 3.95 (s, 2H, CH₂Ph), 5.51 (s, 1H,OH), 6.88 (d, 1H, J=2.05 Hz), 6.95 (m, 2H), 6.97-7.26 (m, 11H). MS (EI):m/z=502 (40), 501 (100), 458 (4), 367 (10), 327 (7), 307 (8), 263 (8),91 (43). HR-MS (EI): Calcd. for C₃₆H₃₉NO: 501.303164. Found: 501.303902.

3-(3′-Benzyl-4″-(cyanomethoxy)-2,3″-diisobutyl-1,1′4′1″-terpehnyl-4-yl)propanenitrile(57)

[0219] To a suspension of 116.5 mg (232 μmol)3-(3′-Benzyl-4″-hydroxy-2,3″-diisobutyl-1,1′:4′,1″-terphenyl-4-yl)propanenitrile(56) and 46.8 mg (0.34 mmol, 1.46 eq.) K₂CO₃ in 12 ml acetone 0.15 ml(2.37 mmol, 10.22 eq.) chloroacetonitrile was added. The resultingmixture was stirred for 40 h at 55° C. and then added to 40 ml of amixture of brine/water (1+1). After extraction with EtOAc the combinedorg. fractions were washed with brine, dried over MgSO₄ and evaporated.Column chromatography (hexanes/EtOAc (2+1)) yielded 114.7 mg (212 μmol,91.43%)3-(3′-Benzyl-4″-(cyanomethoxy)-2,3″-diisobutyl-1,1′:4′,1″-terphenyl-4-yl)propanenitrile(57) as a colorless oil. R_(f) (hexanes/EtOAc (2+1)) 0.40. ¹H-NMR (500MHz, CDCl₃): δ=0.71 (d, 6H, J=6.62 Hz, 2*CH₃), 0.85 (d, 6H, J=6.62 Hz,2*CH₃), 1.65 (m, 1H, CH), 1.81 (m, 1H, CH), 2.45 (d, 2H, J=7.41 Hz,CH₂), 2.46 (d, 2H, J=7.41 Hz, CH₂), 2.62 (t, 2H, J=7.57 Hz, CH₂CH₂CN),2.94 (t, 2H, J=7.57 Hz, CH₂CH₂CN), 3.96 (s, 2H, CH₂Ph), 4.79 (s, 2H,OCH₂CN), 6.88 (d, 1H, J=8.51 Hz), 6.94 (m, 2H), 7.02-7.19 (m, 11H).¹³C-NMR (125 MHz, CDCl₃): δ=19.79, 22.81, 22.90, 29.36, 29.95, 31.74,39.19, 39.51, 42.45, 54.17, 111.70, 115.72, 119.60, 125.80, 126.19,127.65, 128.29, 128.65, 129.05, 129.06, 130.27, 130.37, 130.97, 131.17,132.00, 133.07, 136.25, 137.17, 138.11, 138.12, 140.20, 140.39, 141.20,141.36, 141.87, 154.20. MS (EI): m/z=540 (7), 447 (37), 446 (100), 77(13). HR-MS (EI): Calcd. for C₃₈H₄₀N₂O: 540.314063. Found: 540.314306.

3-(3′-Benzyl-4″-(cyanomethoxy)-2,3″-diisobutyl-1,1′4′1″-terphenyl-4-yl)propanoicacid (58)

[0220] To a solution of 86.4 mg (159.78 μmol)3-(3′-Benzyl-4″-(cyanomethoxy)-2,3″-diisobutyl-1,1′:4′,1″-terphenyl-4-yl)propanenitrile(57) in 6 ml methanol and 6 ml THF 3 ml (24.90 mmol, 155 eq.) 25% aq.NaOH-solution was added. The resulting mixture was refluxed for 24 h andthen cooled to 0° C. After acidifying to pH 2 by adding 1 N aq.HCl-solution brine was added and the mixture was extracted with THF. Thecomb. org. fractions were washed twice with brine, dried over MgSO₄ andevaporated. Column chromatography (first CH₂Cl₂/MeOH (4+1), thenEtOAc/HOAc (95+5)) yielded 70.9 mg (122.5 μmol, 76.67%)3-(3′-Benzyl-4″-(carboxymethoxy)-2,3″-diisobutyl-1,1′:4′,1″-terphenyl-4-yl)propanoicacid (58) as a white solid. R_(f) (EtOAc/HOAc (95+5))=0.76. ¹H-NMR (500MHz, d₄-MeOH+1% d₄-HOAc): δ=0.83 (d, 6H, J=6.62 Hz, 2*CH₃), 1.02 (d, 6H,J=6.62 Hz, 2*CH₃), 1.76 (m, 1H, CH), 2.07 (m, 1H, CH), 2.60 (d, 2H,J=7.25 Hz, CH₂), 2.68 (d, 2H, J=7.25 Hz, CH₂), 2.77 (t, 2H, J=7.57 Hz,CH₂CH₂CO₂H), 3.06 (t, 2H, J=7.57 Hz, CH₂CH₂CO₂H), 4.14 (s, 2H, CH₂Ph),4.79 (s, 2H, OCH₂CO₂H), 6.99 (d, 1H, J=8.36 Hz), 7.10 (m, 2H), 7.21-7.33(m, 10H), 7.39 (d, 1H, J=7.72 Hz). ¹³C-NMR (125 MHz, d₄-MeOH+1%d₄-HOAc): δ=20.89, 22.85, 23.04, 29.82, 30.66, 30.92, 31.78, 35.38, 36,89, 40.01, 40.52, 44.83, 112.38, 126.21, 126.74, 126.81, 128.36, 128.88,129.30, 129.76, 131.08, 131.17, 131.31, 132.74, 133.18, 135.33, 139.16,140.26, 140.92, 141.37, 141.81, 142.40, 143.14, 156.93, 160.58, 171.38,178.30. MS (ESI): 580 (10), 579 (42), 578 (100), 326 (10), 312 (19), 289(26), 260 (15), 186 (12), 173 (10). HR-MS (FAB): Calcd. for C₃₈H₄₂O₅:578.303225. Found: 578.303100.

[0221] Bis-ammonia-salt of 58: ¹H-NMR (500 MHz, d₄-MeOH): δ=0.69 (d, 6H,J=6.62 Hz, 2*CH₃), 0.87 (d, 6H, J=6.62 Hz, 2*CH₃), 1.61 (m, 1H, CH),1.93 (m, 1H, CH), 2.45 (d, 2H, J=7.25 Hz, CH₂), 2.55 (d, 2H, J=7.09 Hz,CH₂), 2.60 (t, 2H, J=7.41 Hz, CH₂CH₂CO₂NH₄), 2.92 (t, 2H, J=7.72 Hz,CH₂CH₂CO₂NH₄), 3.99 (s, 2H, CH₂Ph), 4.48 (s, 2H, OCH₂CO₂NH₄), 6.84 (d,1H, J=8.36 Hz), 6.94-6.99 (m, 3H), 7.06 (dd, 1H, J₁=8.20 Hz, J₂=2.36Hz), 7.07-7.19 (m, 8H), 7.24 (d, 1H, J=7.72 Hz). MS (FAB): 579 (11), 578(21), 454 (9), 279 (10), 220 (10), 219 (54), 195 (34), 155 (38), 135(26), 119 (100). HR-MS (FAB): Calcd. for C₃₈H₄₂O₅: 578.303225. Found:578.303000.

[0222] Synthesis Following the Presentation in FIG. 7, Scheme 7

[0223] Synthesis of theisobutyl-1-naphthalene-isobutyl-terphenyl-derivative 3.

(5-Bromo-2-methoxy-phenyl)-napthalen-1-yl-methanol (62)

[0224] To a solution of 1.70 ml (12.22 mmol) 1-Bromonaphthalene (61) in40 ml dry THF 7.64 ml (12.22 mmol, 1.00 eq.) of a 1.6 M solution ofn-Butyllithium in hexanes were added at −78° C. via syringe. Afterstirring this mixture for 1 h at −78° C. a solution of 2.63 g (12.23mmol, 1.00 eq.) 4-bromo-anisaldehyde (60) in 30 ml dry THF was addeddropwise via a dropping funnel. The resulting mixture was stirred foranother 60 min at −78° C., then for 2 h at −30° C. and finally 15 h atr.t.. After quenching the reaction with 1 M aq. HCl-solution and addingether the org. phase was washed subsequently with water and brine beforeit was dried over MgSO₄ and evaporated. Column chromatography (CH₂Cl₂)yielded 3.70 g (10.77 mmol, 88.15%)(5-Bromo-2-methoxy-phenyl)-napthalen-1-yl-methanol (62) as pale greenishfoam. R_(f) (CH₂Cl₂)=0.37. ¹H-NMR (500 MHz, CDCl₃): δ=3.84 (s, 3H, OMe),6.80 (d, J=8.51 Hz, 1H), 6.81 (s, 1H, HO—CH), 7.18 (d, 1H, J=2.68 Hz),7.34 (dd, 1H, J₁=8.82 Hz, J₂=2.52 Hz), 7.42-7.48 (m, 3H), 7.55 (d, 1H,J=7.09 Hz), 7.79 (d, 1H, J=8.20 Hz), 7.83-7.87 (m, 1H), 7.96-8.00 (m,1H). MS (EI): m/z=345 (14), 344 (76), 343 (17), 342 (77), 326 (14), 325(12), 324 (14), 311 (10), 309 (10), 245 (25), 217 (12), 215 (88), 213(84), 202 (19), 201 (12), 157 (18), 155 (37), 141 (21), 129 (66), 128(100), 127 (42), 108 (12), 101 (24), 77 (14), 63 (11). HR-MS (EI):Calcd. for C₁₈H₁₅BrO₂: 342.025541. Found: 342.025182.

1-(5-Bromo-2-methoxy-benzyl)-naphthalene (63)

[0225] 3.06 g (80.89 mmol, 10.48 eq.) NAB₄ (granules) were added slowlyto 50 ml Trifluoroacetic acid at 0° C. To this mixture a solution of2.65 g (7.72 mmol) (5-Bromo-2-methoxy-phenyl)-napthalen-1-yl-methanol(62) in 30 ml dry CH₂Cl₂ was added which led to an brownish mixture.After stirring this mixture for 19 h at r.t. it was diluted with waterand cooled again to 0° C. At this temperature NaOH-pellets were addedcarefully to adjust the pH to 10 before the solution was extracted withether. The comb. org. fractions. were washed with brine, dried overNa₂SO₄ and evaporated. Column chromatography (CH₂Cl₂) yielded 2.42 g(7.39 mmol, 95.72%) 1-(5-Bromo-2-methoxy-benzyl)-naphthalene (63) as apale yellow oil. R_(f) (CH₂Cl₂)=0.73. ¹H-NMR (400 MHz, CDCl₃): δ=3.84(s, 3H, OMe), 4.35 (s, 2H), 6.76 (d, 1H, J=8.72 Hz), 6.91 (d, 1H, J=2.53Hz), 7.20 (dm, 1H, J₁=6.82 Hz), 7.26 (dd, 1H, J₁=8.84 Hz, J₂=2.53 Hz),7.38 (m, 1H), 7.41-7.49 (m, 2H), 7.74 (d, 1H, J=8.34 Hz), 7.84 (m, 1H),7.91 (m, 1H). MS (EI): m/z=329 (18), 328 (97), 327 (20), 326 (100), 248(16), 247 (35), 232 (22), 231 (25), 216 (20), 215 (41), 203 (17), 202(25), 142 (21), 141 (61), 115 (10), 101 (14). HR-MS (EI): Calcd. forC₁₈H₁₅BrO: 326.030626. Found: 326.030567.

2-(4-Methoxy-3-naphthalen-1-ylmethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(64)

[0226] A solution of 839.2 mg (2.56 mmol)1-(5-Bromo-2-methoxy-benzyl)-naphthalene (63), 689.5 mg (2.72 mmol, 1.06eq.) bis(pinacolato)diboron, 768.8 mg (7.83 mmol, 3.06 eq.) KOAc and106.8 mg (130.7 μmol, 0.05 eq.) PdCl₂dppf*CH₂Cl₂ in 16 ml DMSO washeated at 85° C. for 5 h. After that water was added and the mixture wasextracted with CH₂Cl₂. The comb. org. fractions were washed with water,dried over MgSO₄ and evaporated. Column chromatography (hexanes/EtOAc(9+1)) yielded 638.5 mg (1.71 mmol, 66.64%)2-(4-Methoxy-3-naphthalen-1-ylmethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(64) as a white solid. R_(f) (hexanes/EtOAc (9+1)): 0.19. ¹H-NMR (500MHz, CDCl₃): δ=1.26 (s, 12H, 4*CH₃), 3.79 (s, 3H, OMe), 4.40 (s, 2H),6.90 (d, 1H, J=8.21 Hz), 7.04 (dd, 1H, J₁=7.07 Hz, J₂=1.01 Hz), 7.31 (m,1H), 7.40-7.49 (m, 2H), 7.55 (d, 1H, J=1.64 Hz), 7.68 (m, 2H), 7.82 (m,1H), 8.11 (m, 1H). MS (EI): m/z=375 (27), 374 (100), 373 (23), 274 (30),273 (12), 259 (17), 241 (11), 216 (11), 215 (27), 147 (46), 146 (12),142 (12), 141 (32), 117 (17), 83 (28). HR-MS (EI): Calcd. for C₂₄H₂₇BO₃:373.208958. Found: 374.206159.

3-(2-Isobutyl-4′-methoxy-3′-naphthalen-1-ylmethyl-biphenyl-4-yl)propionitrile(65)

[0227] 452 mg (1.35 mmol)4-(2-Cyanoethyl)-2-isobutylphenyl-trifluormethanesulfonate (6), 637.8 mg(1.70 mmol, 1.26 eq.)2-(4-Methoxy-3-naphthalen-1-ylmethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(64) and 236.8 mg (205 μmol, 0.15 eq.) Pd(Ph₃P)₄ were dissolved in 20 mlDME/EtOH (9+1). To this yellow solution 1.35 ml (2.70 mmol, 2 eq.) of a2 M aq. Na₂CO₃-solution was added and the resulting mixture was heatedat 80° C. for 15 h. After concentrating the mixture in vacuo the residuewas taken up in water and extracted with CH₂Cl₂. The comb. org.fractions were dried over MgSO₄ and evaporated. Column chromatography(hexanes/EtOAc (3+1)) yielded 513.8 mg (1.19 mmol, 87.78%)3-(2-Isobutyl-4′-methoxy-3′-naphthalen-1-ylmethyl-biphenyl-4-yl)propionitrile(65) as a clear oil. R_(f) (hexanes/EtOAc (3+1))=0.40. ¹H-NMR (500 MHz,CDCl₃): δ=0.51 (d, 6H, J=6.62 Hz, 2*CH₃), 1.42 (m, 1H, CH), 2.17 (d, 2H,J=7.25 Hz, CH₂), 2.56 (t, 2H, J=7.41 Hz, CH₂CH₂CN), 2.87 (t, 2H, J=7.41Hz, CH₂CH₂CN), 3.91 (s, 3H, OCH₃), 4.42 (s, 2H, CH₂Naphthyl), 6.71 (d,1H, J=2.21 Hz), 6.94 (m, 3H), 7.00 (d, 1H, J=7.72 Hz), 7.04 (dd, 1H,J₁=8.36 Hz, J₂=2.36 Hz), 7.22 (m, 1H), 7.35 (m, 1H), 7.41 (m, 2H), 7.69(d, 1H, J=8.20 Hz), 7.81 (m, 1H), 7.97 (m, 1H). MS (EI): m/z=434 (16),433 (48), 336 (9), 335 (56), 294 (11), 293 (83), 292 (17), 277 (9), 265(20), 264 (100), 253 (29). HR-MS (EI): Calcd. for C₃₁H₃₁NO: 433.240564.Found: 433.241264.

3-(4′-Hydroxy-2-isobutyl-3′-naphthalen-1-ylmethyl-biphenyl-4-yl)-propionitrile(66)

[0228] 2.55 ml (2.55 mmol, 3.00 eq.) of a 1 M solution of BBr₃ in CH₂Cl₂was added to a solution of 367.3 mg (0.85 mmol)3-(2-Isobutyl-4′-methoxy-3′-naphthalen-1-ylmethyl-biphenyl-4-yl)propionitrile(65) in 40 ml dry CH₂Cl₂ at 0° C. via syringe. After that the solutionwas stirred for 2 h at 0° C. and then for 14 h at r.t. The reactionmixture was then added to water and extracted with CH₂Cl₂. The comb.org. fractions were dried over MgSO₄ and evaporated. Columnchromatography (hexanes/EtOAc (2+1)) yielded 334.9 mg (0.80 mmol,93.91%)3-(4′-Hydroxy-2-isobutyl-3′-naphthalen-1-ylmethyl-biphenyl-4-yl)-propionitrile(66) as an oily white solid. R_(f) (hexanes/EtOAc (2+1))=0.36. ¹H-NMR(500 MHz, CDCl₃): δ=0.56 (d, 6H, J=6.62 Hz, 2*CH₃), 1.48 (m, 1H, CH),2.26 (d, 2H, J=7.41 Hz, CH₂), 2.58 (t, 2H, J=7.41 Hz, CH₂CH₂CN), 2.89(t, 2H, J=7.41 Hz, CH₂CH₂CN), 4.44 (s, 2H, CH₂Naphthyl), 4.80 (s, br.,1H, OH), 6.83 (d, 1H, J=8.20 Hz), 6.85 (d, 1H, J=2.05 Hz), 6.96-7.00 (m,3 H), 7.04 (d, 1H, J=7.41 Hz), 7.25 (m, 1H), 7.36 (m, 1H), 7.44 (m, 2H),7.73 (d, 1H, J=8.20 Hz), 7.83 (m, 1H), 8.03 (m, 1H). MS (EI): m/z=419(2), 335 (14), 293 (22), 253 (8), 161 (18), 160 (100), 91 (18). HR-MS(EI): Calcd. for C₃₀H₂₉NO: 419.224914. Found: 419.225626.

Trifluoro-methanesulfonic acid4′-(2-cyano-ethyl)-2′-isobutyl-3-naphthalen-1-ylmethyl-biphenyl-4-yl-ester(67)

[0229] 0.27 ml (1.61 mmol, 1.80 eq.) triflic anhydride was added to asolution of 374.0 mg (0.89 mmol)3-(4′-Hydroxy-2-isobutyl-3′-naphthalen-1-ylmethyl-biphenyl-4-yl)-propionitrile(66) in 10 ml pyridine at 0° C. The resulting mixture was stirred at 0°C. for 60 min and then at r.t. for 19 h. After that water was added andthe mixture was extracted with ether. The comb. org. fractions werewashed with brine, dried over MgSO₄ and evaporated. Columnchromatography (hexanes/EtOAc (1+1)) yielded 441.7 mg (0.80 mmol,89.81%) Trifluoro-methanesulfonic acid4′-(2-cyano-ethyl)-2′-isobutyl-3-naphthalen-1-ylmethyl-biphenyl-4-yl-ester(67) as a colorless oil. R_(f) (hexanes/EtOAc (1+1))=0.64. ¹H-NMR (500MHz, CDCl₃): δ=0.43 (d, 6H, J=6.62 Hz, 2*CH₃), 1.31 (m, 1H, CH), 2.04(d, 2H, J=7.25 Hz, CH₂), 2.55 (t, 2H, J=7.41 Hz, CH₂CH₂CN), 2.86 (t, 2H,J=7.41 Hz, CH₂CH₂CN), 4.52 (s, 2H, CH₂Naphthyl), 6.74 (d, 1H, J=2.21Hz), 6.91-6.97 (m, 3 H), 7.13 (dd, 1H, J₁=8.36 Hz, J₂=2.21 Hz), 7.28 (m,1H), 7.34-7.45 (m, 4H), 7.75 (m, 1H), 7.78 (m, 1H), 7.82 (m, 1H), MS(EI): m/z=551 (18), 418 (9), 335 (14), 293 (22), 161 (16), 160 (100),141 (14), 91 (16), HR-MS (EI): Calcd. for C₃₁H₂₉F₃NO₃S: 552.182025.Found: 551.174200.

3-(3,2″-Diisobutyl-4-methoxy-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile(68)

[0230] 439.6 mg (0.80 mmol) Trifluoro-methanesulfonic acid4′-(2-cyano-ethyl)-2′-isobutyl-3-naphthalen-1-ylmethyl-biphenyl-4-yl-ester(67), 266.2 mg (0.92 mmol, 1.15 eq.)2-(3-isobutyl-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(11, FIG. 6) and 140.4 mg (121.4 μmol, 0.15 eq.) Pd(Ph₃P)₄ weredissolved in 15 ml DME/EtOH (9+1). To this yellow solution 0.80 ml (1.60mmol, 2.00 eq.) of a 2 M aq. Na₂CO₃-solution was added and the resultingmixture was heated at 80° C. for 9 h. After concentrating the mixture invacuo the residue was taken up in water and extracted with CH₂Cl₂. Thecomb. org. fractions were dried over MgSO₄ and evaporated. Columnchromatography (CH₂Cl₂) yielded 426.5 mg (0.75 mmol, 94.23%)3-(3,2″-Diisobutyl-4-methoxy-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile(68) as a clear oil. R_(f) (hexanes/EtOAc (6+1))=0.12. ¹H-NMR (500 MHz,CDCl₃): δ=0.52 (d, 6H, J=6.62 Hz, 2*CH₃), 0.77 (d, 6H, J=6.62 Hz,2*CH₃), 1.47 (m, 1H, CH), 1.74 (m, 1H, CH), 2.24 (d, 2H, J=7.41 Hz,CH₂), 2.41 (d, 2H, J=7.25 Hz, CH₂), 2.58 (t, 2H, J=7.41 Hz, CH₂CH₂CN),2.90 (t, 2H, J=7.41 Hz, CH₂CH₂CN), 3.79 (s, 3H, OCH₃), 4.39 (s, 2H,CH₂Naphthyl), 6.83 (d, 1H, J=8.36 Hz), 6.96 (m, 2H), 6.99 (dd, 1H,J₁=7.88 Hz, J₂=1.89 Hz), 7.08 (d, 1H, J=7.57 Hz), 7.11-7.17 (m, 3H),7.22 (m, 1H), 7.30-7.35 (m, 3H), 7.38 (m, 1H), 7.67 (dm, 1H, J=7.88 Hz),7.72 (dm, 1H, J=8.20 Hz), 7.78 (dm, 1H, J=8.20 Hz). MS (EI): m/z=565(14), 452 (11), 410 (10), 404 (19), 403 (59), 349 (24), 306 (10), 290(13), 247 (35), 191 (13), 142 (14), 141 (100). HR-MS (EI): Calcd. forC₄₁H₄₃NO: 565.334464. Found: 565.334575.

3-(4-Hydroxy-3,2″-diisobutyl-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile(69)

[0231] 1.44 ml (1.44 mmol, 3.00 eq.) of a 1 M solution of BBr₃ in CH₂Cl₂was added to a solution of 270.8 mg (0.48 mmol)3-(3,2″-Diisobutyl-4-methoxy-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile(68) in 25 ml dry CH₂Cl₂ at 0° C. via syringe. After that the solutionwas stirred for 60 min at 0° C. and then for 12 h at r.t. The reactionmixture was then added to water and extracted with CH₂Cl₂. The comb.org. fractions were dried over MgSO₄ and evaporated. Columnchromatography (hexanes/EtOAc (2+1)) yielded 261.9 mg (0.48 mmol,98.89%)3-(4-Hydroxy-3,2″-diisobutyl-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile(69) as a colorless oil. R_(f) (hexanes/EtOAc (2+1))=0.40. ¹H-NMR (500MHz, CDCl₃): δ=0.53 (d, 6H, J=6.62 Hz, 2*CH₃), 0.79 (d, 6H, J=6.62 Hz,2*CH₃), 1.47 (m, 1H, CH), 1.73 (m, 1H, CH), 2.24 (d, 2H, J=7.41 Hz,CH₂), 2.39 (d, 2H, J=7.09 Hz, CH₂), 2.58 (t, 2H, J=7.41 Hz, CH₂CH₂CN),2.90 (t, 2H, J=7.41 Hz, CH₂CH₂CN), 4.38 (s, 2H, CH₂Naphthyl), 4.58 (s,1H, OH), 6.76 (d, 1H, J=8.04 Hz), 6.97 (m, 2H), 7.00 (m, 1H), 7.08-7.16(m, 5H), 7.30-7.41 (m, 4H), 7.67 (dm, 1H, J=8.04 Hz), 7.72 (dm, 1H,J=8.51 Hz), 7.78 (dm, 1H, J=8.04 Hz). MS (EI): m/z=553 (11), 552 (43),551 (100), 141 (49). HR-MS (EI): Calcd. for C₄₀H₄₁NO: 551.318814. Found:551.318350.

3-(4-Cyanomethoxy-3,2″-diisobutyl-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile(70)

[0232] To a suspension of 374.5 mg (0.68 mmol)3-(4-Hydroxy-3,2″-diisobutyl-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile(70) and 498.2 mg (3.61 mmol, 5.30 eq.) K₂CO₃ in 20 ml acetone 0.43 ml(6.79 mmol, 9.99 eq.) chloroacetonitrile was added. The resultingmixture was stirred for 24 h at 55° C. and then added to 100 ml of amixture of brine/water (1+1). After extraction with EtOAc the combinedorg. fractions were washed with brine, dried over MgSO₄ and evaporated.Column chromatography (hexanes/EtOAc (2+1)) yielded 395.3 mg (0.67 mmol,98.39%)3-(4-Cyanomethoxy-3,2″-diisobutyl-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile(71) as a colorless oil. R_(f) (hexanes/EtOAc (2+1))=0.37. ¹H-NMR (500MHz, CDCl₃): δ=0.55 (d, 6H, J=6.62 Hz, 2*CH₃), 0.75 (d, 6H, J=6.62 Hz,2*CH₃), 1.48 (m, 1H, CH), 1.68 (m, 1H, CH), 2.26 (d, 2H, J=7.25 Hz,CH₂), 2.40 (d, 2H, J=7.09 Hz, CH₂), 2.59 (t, 2H, J=7.41 Hz, CH₂CH₂CN),2.90 (t, 2H, J=7.41 Hz, CH₂CH₂CN), 4.36 (s, 2H, CH₂Naphthyl), 4.75 (s,2H, OCH₂CN), 6.89 (d, 1H, J=8.51 Hz), 6.98-7.02 (m, 3H), 7.08-7.18 (m,4H), 7.30-7.44 (m, 5H), 7.67 (dm, 1H, J=8.67 Hz), 7.72 (dm, 1H, J=8.20Hz), 7.79 (dm, 1H, J=8.04 Hz). MS (EI): m/z=592 (12), 591 (50), 590(100), 551 (5), 374 (4), 141 (44). HR-MS (EI): Calcd. for C₄₂H₄₂N₂O:590.329713. Found: 590.329441.

3-(3,2″-Diisobutyl-4-methoxycarbonylmethoxy-2′-naphthalen-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionicmethylester (71)

[0233] A solution of 140.0 mg (0.24 mmol)3-(4-Cyanomethoxy-3,2″-diisobutyl-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile(70) in 22 ml methanol was saturated with dried hydrogen chloride atr.t. Then the mixture was refluxed for 1.5 h under continuous passing ofhydrogen chloride. After that nitrogen was passed through the solutionat r.t. before ice-cold water was added to the mixture. After extractingthe mixture with ether the comb. org. fractions were dried over Na₂SO₄and evaporated. Column chromatography (hexanes/EtOAc (2+1)) yielded139.3 mg (0.21 mmol, 88.33%)3-(3,2″-Diisobutyl-4-methoxycarbonylmethoxy-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionicacid methyl ester (71) as a colorless oil. R_(f) (hexanes/EtOAc(2+1))=0.45. ¹H-NMR (500 MHz, CDCl₃): δ=0.52 (d, 6H, J=6.62 Hz, 2*CH₃),0.77 (d, 6H, J=6.62 Hz, 2*CH₃), 1.46 (m, 1H, CH), 1.78 (m, 1H, CH), 2.23(d, 2H, J=7.41 Hz, CH₂), 2.46 (d, 2H, J=7.25 Hz, CH₂), 2.59 (t, 2H,J=7.41 Hz, CH₂CH₂CO₂Me), 2.89 (t, 2H, J=7.41 Hz, CH₂CH₂CO₂Me), 3.63 (s,3H, CO₂Me), 3.76 (s, 3H, CO₂Me), 4.37 (s, 2H, CH₂Naphthyl), 4.62 (s, 2H,OCH₂CO₂Me), 6.68 (d, 1H, J=8.36 Hz), 6.93-6.98 (m, 3H), 7.01-7.05 (m,1H), 7.12-7.19 (m, 4H), 7.30-7.40 (m, 4H), 7.66 (dm, 1H, J=8.20 Hz),7.72 (dm, 1H, J=8.51 Hz), 7.78 (dm, 1H, J=8.51 Hz). ¹³C-NMR (125 MHz,CDCl₃): δ=22.22, 22.46, 28.65, 29.32, 30.62, 35.68, 36.62, 39.35, 41.87,51.55, 52.08, 65.53, 110.92, 123.99, 125.32, 125.37, 125.41, 125.75,126.78, 126.94, 127.28, 127.50, 128.50, 129.78, 129.90, 130.11, 130.47,131.21, 131.92, 132.17, 133.79, 134.28, 137.10, 137.58, 139.04, 139.25,140.00, 140.02, 140.83, 155.16, 169.57, 173.36. MS (EI): m/z=658 (15),657 (50), 656 (100), 141 (38). HR-MS (EI): Calcd. for C₄₄H₄₈O₅:656.350175. Found: 656.350300.

3-(4-(Carboxymethoxy)-3,2″-diisobutyl-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionicacid (72)

[0234] To a solution of 50.6 mg (77.03 μmol)3-(3,2″-Diisobutyl-4-methoxycarbonylmethoxy-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionicacid methyl ester (71) in 8 ml 1.4-dioxane 2.8 ml (23.24 mmol, 302 eq.)25% aq. NaOH-solution and 2.8 ml (4.31 mmol, 56 eq.) 40% aq. solution ofBu₄NOH were added. The resulting mixture was refluxed for 27 h and thencooled to 0° C. Acidification to pH 1 by adding 1 N aq. HCl-solution ledto a white precipitate which was obtained by filtration. A filtrationover silica gel with EtOAc/HOAc (95+5)) as an eluent and a followinglyophilization of the obtained oily product from a solution in CH₃CN andaq. NH₃-solution yielded 51.0 mg (76.9 μmol, 100%) of thebisammonia-salt of3-(4-(Carboxymethoxy)-3,2″-diisobutyl-2′-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionicacid (72) as a white solid. R_(f) (CH₂Cl₂/MeOH (10+1))=0.20. ¹H-NMR (500MHz, d₄-MeOH): δ=0.47 (d, 6H, J=6.62 Hz, 2*CH₃), 0.79 (d, 6H, J=6.62 Hz,2*CH₃), 1.38 (m, 1H, CH), 1.81 (m, 1H, CH), 2.22 (d, 2H, J=7.25 Hz,CH₂), 2.51 (d, 2H, J=7.25 Hz, CH₂), 2.56 (t, 2H, J=7.41 Hz,CH₂CH₂CO₂NH₄), 2.87 (t, 2H, J=7.41 Hz, CH₂CH₂CO₂NH₄), 4.40 (s, 2H,CH₂Naphthyl), 4.49 (s, 2H, OCH₂CO₂NH₄), 6.88 (d, 1H, J=8.83 Hz), 6.91(d, 1H, J=1.73 Hz), 6.97-7.03 (m, 3H), 7.10-7.13 (m, 2H), 7.19-7.23 (m,2H), 7.32 (d, 1H, J=7.72 Hz), 7.34-7.42 (m, 3H), 7.71 (m, 2H), 7.81 (m,1H). ¹³C-NMR (125 MHz, d₄-MeOH): δ=22.66, 22.99, 29.74, 30.48, 32.01,37.39, 37.76, 40.52, 43.18, 68.63, 112.78, 125.23, 126.39, 126.57,126.60, 126.88, 127.99, 128.12, 128.29,128.81, 129.63, 130.97, 131.03,131.06, 131.41, 132.23, 132.87, 133.32, 133.81, 134.80, 135.52, 136.66,138.69, 139.06, 140.21, 141.01, 141.37, 141.78, 142.29, 157.64. MS(FAB+): m/z=669 (18), 668 (45), 667 (100), 651 (13), 628 (12), 609 (11),347 (11), 309 (19), 301 (10), 280 (18), 279 (95), 195 (20), 193 (20),177 (15), 155 (32), 149 (66), 141 (26), 135 (21), 119 (70). HR-MS(FAB+): Calcd. for C₄₂H₄₄O₅: 628.318875. Found: 628.318800.

[0235] Synthesis Following the Presentation in FIG. 8, Scheme 8

[0236] Synthesis of the 1-naphthalene-bisisobutyl-terphenyl-derivative4.

3-(2,3′-Diisobutyl-4′-methoxy-biphenyl-4-yl)propionitrile (73)

[0237] 294.8 mg (0.88 mmol)4-(2-Cyanoethyl)-2-isobutylphenyl-trifluormethanesulfonate (6), 312.9 mg(1.08 mmol, 1.23 eq.)2-(3-Isobutyl-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(11) and 156 mg (135 μmol, 0.15 eq.) Pd(Ph₃P)₄ were dissolved in 20 mlDME/EtOH (9+1). To this yellow solution 0.88 ml (1.76 mmol, 2.00 eq.) ofa 2 M aq. Na₂CO₃-solution was added and the resulting mixture was heatedat 80° C. for 17 h. After concentrating the mixture in vacuo the residuewas taken up in water and extracted with CH₂Cl₂. The comb. org.fractions were dried over MgSO₄ and evaporated. Column chromatography(CH₂Cl₂) yielded 305.9 mg (0.88 mmol, 99.45%)3-(2,3′-Diisobutyl-4′-methoxy-biphenyl-4-yl)propionitrile (73) as aclear oil. R_(f) (CH₂Cl₂)=0.68. ¹H-NMR (500 MHz, CDCl₃): δ=0.67 (d, 6H,J=6.62 Hz, 2*CH₃), 0.85 (d, 6H, J=6.62 Hz, 2*CH₃), 1.61 (m, 1H, CH),1.89 (m, 1H, CH), 2.44 (d, 2H, J=7.25 Hz, CH₂), 2.45 (d, 2H, J=7.25 Hz,CH₂), 2.59 (t, 2H, J=7.41 Hz, CH₂CH₂CN), 2.91 (t, 2H, J=7.41 Hz,CH₂CH₂CN), 3.79 (s, 3H, OCH₃), 6.80 (d, 1H, J=8.36 Hz), 6.94 (d, 1H,J=2.21 Hz), 6.98-7.04 (m, 3H), 7.09 (d, 1H, J=7.57 Hz). MS (EI): m/z=350(23), 349 (90), 307 (10), 306 (35), 290 (39), 250 (15), 248 (17), 247(100), 246 (24), 209 (21), 191 (16), 178 (10), 147 (10), 145 (17), 144(19), 117 (13), 105 (25), 83 (11), 57 (18). HR-MS (EI): Calcd. forC₂₄H₃₁NO: 349.240564. Found: 349.240765.

3-(4′-Hydroxy-2,3′-diisobutyl-biphenyl-4-yl)-propionitrile (74)

[0238] 2.37 ml (2.37 mmol, 3.00 eq.) of a 1 M solution of BBr₃ in CH₂Cl₂was added to a solution of 275.6 mg (0.79 mmol)3-(2,3′-Diisobutyl-4′-methoxy-biphenyl-4-yl)propionitrile (73) in 25 mldry CH₂Cl₂ at 0° C. via syringe. After that the solution was stirred for3 h at 0° C. and then for 10 h at r.t. The reaction mixture was thenadded to water and extracted with CH₂Cl₂. The comb. org. fractions weredried over MgSO₄ and evaporated. Column chromatography (hexanes/EtOAc(2+1)) yielded 174.9 mg (0.52 mmol, 65.99%)3-(4′-Hydroxy-2,3′-diisobutyl-biphenyl-4-yl)-propionitrile (74) as anoily white solid. R_(f) (hexanes/EtOAc (2+1))=0.38. ¹H-NMR (500 MHz,CDCl₃): δ=0.69 (d, 6H, J=6.62 Hz, 2*CH₃), 0.92 (d, 6H, J=6.62 Hz,2*CH₃), 1.63 (m, 1H, CH), 1.93 (m, 1H, CH), 2.45 (d, 2H, J=7.25 Hz,CH₂), 2.47 (d, 2H, J=7.25 Hz, CH₂), 2.62 (t, 2H, J=7.41 Hz, CH₂CH₂CN),2.94 (t, 2H, J=7.41 Hz, CH₂CH₂CN), 4.60 (s, br., 1H, OH), 6.75 (d, 1H,J=8.36 Hz), 6.92-6.96 (m, 2H), 7.01-7.06 (m, 2H), 7.11 (d, 1H, J=7.57Hz). MS (EI): m/z=336 (24), 335 (100), 292 (18), 251 (10), 236 (35), 209(12), 196 (10), 195 (48), 178 (10), 165 (10). HR-MS (EI): Calcd. forC₂₃H₂₉NO: 335.224914. Found: 335.225330.

Trifluoro-methanesulfonic acid4′-(2-cyano-ethyl)-3,2′-diisobutyl-biphenyl-4-yl-ester (75)

[0239] 0.16 ml (0.95 mmol, 1.83 eq.) triflic anhydride was added to asolution of 173.2 mg (0.52 mmol)3-(4′-Hydroxy-2,3′-diisobutyl-biphenyl-4-yl)-propionitrile (74) in 10 mlpyridine at 0° C. The resulting mixture was stirred at 0° C. for 3 h andthen at r.t. for 14 h. After that water was added and the mixture wasextracted with ether. The comb. org. fractions were washed with brine,dried over MgSO₄ and evaporated. Column chromatography (hexanes/EtOAc(1+1)) yielded 203.3 mg (0.43 mmol, 83.62%) Trifluoro-methanesulfonicacid 4′-(2-cyano-ethyl)-3,2′-diisobutyl-biphenyl-4-yl-ester (75) as acolorless oil. R_(f) (hexanes/EtOAc (1+1))=0.68. ¹H-NMR (500 MHz,CDCl₃): δ=0.69 (d, 6H, J=6.62 Hz, 2*CH₃), 0.91 (d, 6H, J=6.62 Hz,2*CH₃), 1.59 (m, 1H, CH), 1.94 (m, 1H, CH), 2.42 (d, 2H, J=7.25 Hz,CH₂), 2.58 (d, 2H, J=7.25 Hz, CH₂), 2.63 (t, 2H, J=7.41 Hz, CH₂CH₂CN),2.95 (t, 2H, J=7.41 Hz, CH₂CH₂CN), 7.06-7.16 (m, 5H), 7.25 (d, 1H,J=8.20 Hz). MS (EI): m/z=469 (9), 468 (28), 467 (100), 425 (10), 368(12), 335 (19), 334 (72), 327 (11), 293 (16), 292 (52), 279 (19), 278(39), 251 (12), 250 (19), 248 (11), 237 (17), 236 (16), 235 (15), 233(10), 209 (12), 207 (12), 195 (17), 179 (16), 178 (12), 165 (14), 105(10). HR-MS (EI): Calcd. for C₂₄H₂₈F₃NO₃S: 467.174201. Found:467.173888.

3-(2′,2″-Diisobutyl-4-methoxy-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile(76)

[0240] 202.8 mg (0.43 mmol) Trifluoro-methanesulfonic acid4′-(2-cyano-ethyl)-3,2′-diisobutyl-biphenyl-4-yl-ester (75), 186.7 mg(0.50 mmol, 1.16 eq.)2-(4-Methoxy-3-naphthalen-1-ylmethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(64) and 74.5 mg (64.4 μmol, 0.15 eq.) Pd(Ph₃P)₄ were dissolved in 10 mlDME/EtOH (9+1). To this yellow solution 0.43 ml (0.86 mmol, 2.00 eq.) ofa 2 M aq. Na₂CO₃-solution was added and the resulting mixture was heatedat 80° C. for 22 h. After concentrating the mixture in vacuo the residuewas taken up in water and extracted with CH₂Cl₂. The comb. org.fractions were dried over MgSO₄ and evaporated. Column chromatography(CH₂Cl₂) yielded 194.3 mg (0.34 mmol, 79.86%)3-(2′,2″-Diisobutyl-4-methoxy-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile(76) as a clear oil. R_(f) (hexanes/EtOAc (6+1))=0.23. ¹H-NMR (500 MHz,CDCl₃): δ=0.52 (d, 6H, J=6.62 Hz, 2*CH₃), 0.69 (d, 6H, J=6.62 Hz,2*CH₃), 1.46 (m, 1H, CH), 1.64 (m, 1H, CH), 2.23 (d, 2H, J=7.41 Hz,CH₂), 2.45 (d, 2H, J=7.41 Hz, CH₂), 2.61 (t, 2H, J=7.41 Hz, CH₂CH₂CN),2.93 (t, 2H, J=7.41 Hz, CH₂CH₂CN), 3.91 (s, 3H, OCH₃), 4.44 (s, 2H,CH₂Naphthyl), 6.84 (d, 1H, J=2.21 Hz), 6.95 (d, 1H, J=8.67 Hz),6.97-7.16 (m, 8H), 7.36 (m, 1H), 7.41-7.45 (m, 2H), 7.70 (m, 1H), 7.81(m, 1H), 8.01 (m, 1H). MS (EI): m/z=565 (23), 468 (30), 467 (100), 425(13), 374 (11), 368 (13), 335 (23), 334 (72), 327 (13), 324 (17), 319(31), 293 (22), 292 (55), 279 (14), 278 (45), 277 (13), 276 (17), 264(24), 263 (19), 251 (13), 250 (24), 249 (26), 248 (89), 237 (20), 236(18), 235 (22), 234 (15), 233 (26), 221 (20), 220 (37), 217 (25), 215(31), 179 (71), 178 (57), 165 (30), 160 (20), 142 (22), 141 (62), 115(15), 91 (14), 57 (86), 55 (16). HR-MS (EI): Calcd. for C₄₁H₄₃NO:565.334464. Found: 565.334507.

3-(4-Hydroxy-2′,2″-diisobutyl-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]terphenyl-4″-yl)propionitrile(77)

[0241] 1.02 ml (1.02 mmol, 3.00 eq.) of a 1 M solution of BBr₃ in CH₂Cl₂was added to a solution of 192.9 mg (0.34 mmol)3-(2′,2″-Diisobutyl-4-methoxy-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionitrile(76) in 20 ml dry CH₂Cl₂ at 0° C. via syringe. After that the solutionwas stirred for 3 h at 0° C. and then for 12 h at r.t. The reactionmixture was then added to water and extracted with CH₂Cl₂. The comb.org. fractions were dried over MgSO₄ and evaporated. Columnchromatography (hexanes/EtOAc (2+1)) yielded 117.9 mg (0.21 mmol,62.85%)3-(4-Hydroxy-2′,2″-diisobutyl-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]terphenyl-4″-yl)propionitrile(32) as a colorless oil. R_(f) (hexanes/EtOAc (2+1))=0.37. ¹H-NMR (500MHz, CDCl₃): δ=0.59 (d, 6H, J=6.62 Hz, 2*CH₃), 0.70 (d, 6H, J=6.78 Hz,2*CH₃), 1.50 (m, 1H, CH), 1.65 (m, 1H, CH), 2.32 (d, 2H, J=7.25 Hz,CH₂), 2.47 (d, 2H, J=7.25 Hz, CH₂), 2.62 (t, 2H, J=7.41 Hz, CH₂CH₂CN),2.94 (t, 2H, J=7.41 Hz, CH₂CH₂CN), 4.47 (s, 2H, CH₂Naphthyl), 4.80 (s,1H, OH), 6.86 (d, 1H, J=8.36 Hz), 6.98-7.16 (m, 9H), 7.38 (m, 1H),7.43-7.48 (m, 2H), 7.73 (dm, 1H, J=8.73 Hz), 7.83 (m, 1H), 8.06 (m, 1H).MS (EI): m/z=552 (30), 551 (65), 446 (21), 419 (21), 178 (19), 155 (15),149 (24), 142 (18), 141 (100), 128 (28), 97 (23), 85 (26), 83 (25), 71(39), 69 (30), 57 (74), 55 (35). HR-MS (EI): Calcd. for C₄₀H₄₁NO:551.318814. Found: 551.318768.

3-(4-Cyanomethoxy-2′,2″-diisobutyl-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]terphenyl-4″-yl)propionitrile(78)

[0242] To a suspension of 115.9 mg (0.21 mmol)3-(4-Hydroxy-2′,2″-diisobutyl-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]terphenyl-4″-yl)propionitrile(77) and 166.0 mg (1.20 mmol, 5.72 eq.) K₂CO₃ in 20 ml acetone 0.13 ml(2.05 mmol, 9.78 eq.) α-chloroacetonitrile was added. The resultingmixture was stirred for 40 h at 55° C. and then added to 100 ml of amixture of brine/water (1+1). After extraction with EtOAc the combinedorg. fractions were washed with brine, dried over MgSO₄ and evaporated.Column chromatography (hexanes/EtOAc (2+1)) yielded 96.2 mg (0.16 mmol,77.54%)3-(4-Cyanomethoxy-2′,2″-diisobutyl-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]terphenyl-4″-yl)propionitrile(78) as a colorless oil. R_(f) (hexanes/EtOAC (2+1))=0.33. ¹H-NMR (500MHz, CDCl₃): δ=0.54 (d, 6H, J=6.62 Hz, 2*CH₃), 0.69 (d, 6H, J=6.62 Hz,2*CH₃), 1.47 (m, 1H, CH), 1.64 (m, 1H, CH), 2.24 (d, 2H, J=7.25 Hz,CH₂), 2.45 (d, 2H, J=6.94 Hz, CH₂), 2.62 (t, 2H, J=7.41 Hz, CH₂CH₂CN),2.94 (t, 2H, J=7.41 Hz, CH₂CH₂CN), 4.46 (s, 2H, CH₂Naphthyl), 4.83 (s,2H, OCH₂CN), 6.95 (d, 1H, J=2.05 Hz), 6.99-7.08 (m, 5H), 7.11 (d, 1H,J=7.72 Hz), 7.18-7.22 (m, 2H), 7.33-7.38 (m, 2H), 7.42-7.48 (m, 2H),7.72 (dm, 1H, J=8.36 Hz), 7.83 (m, 1H), 7.99 (m, 1H). MS (EI): m/z=592(11), 591 (46), 590 (100), 550 (14), 142 (10), 141 (77), 57 (20). HR-MS(EI): Calcd. for C₄₂H₄₂N₂O: 590.329713. Found: 590.329806.

3-(2′,2″-Diisobutyl-4′-methoxycarbonylmethoxy-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionicacid methyl ester (79)

[0243] A solution of 89.1 mg (0.15 mmol)3-(4-Cyanomethoxy-2′,2″-diisobutyl-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]terphenyl-4″-yl)propionitrile(78) in 30 ml methanol was saturated with dried hydrogen chloride atr.t. Then the mixture was refluxed for 1 h under continuous passing ofhydrogen chloride. After that nitrogen was passed through the solutionat r.t. before ice-cold water was added to the mixture. After extractingthe mixture with ether the comb. org. fractions were washed with brineand dried over Na₂SO₄ and evaporated. Column chromatography(hexanes/EtOAc (2+1)) yielded 85.4 mg (0.13 mmol, 86.68%)3-(2′,2″-Diisobutyl-4-methoxycarbonylmethoxy-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionicacid methyl ester (79) as a colorless oil. R_(f) (hexanes/EtOAc(2+1))=0.48. ¹H-NMR (500 MHz, CDCl₃): δ=0.51 (d, 6H, J=6.46 Hz, 2*CH₃),0.67 (d, 6H, J=6.46 Hz, 2*CH₃), 1.44 (m, 1H, CH), 1.61 (m, 1H, CH), 2.20(d, 2H, J=7.25 Hz, CH₂), 2.43 (d, 2H, J=7.25 Hz, CH₂), 2.63 (t, 2H,J=7.57 Hz, CH₂CH₂CO₂Me), 2.92 (t, 2H, J=7.57 Hz, CH₂CH₂CO₂Me), 3.65 (s,3H, CO₂Me), 3.80 (s, 3H, CO₂Me), 4.53 (s, 2H, CH₂Naphthyl), 4.73 (s, 2H,OCH₂CO₂Me), 6.81 (d, 1H, J=8.67 Hz), 6.88 (d, 1H, J=1.89 Hz), 6.97-7.07(m, 6H), 7.09 (dd, 1H, J₁=8.04 Hz, J₂=2.05 Hz), 7.28 (m, 1H), 7.36 (m,1H), 7.40-7,44 (m, 2H), 7.70 (dm, 1H, J=8.36 Hz), 7.81 (m, 1H), 8.05 (m,1H). ¹³C-NMR (125 MHz, CDCl₃): δ=22.18, 22.34, 29.27, 29.49, 30.67,32.59, 35.74, 41.94, 42.06, 51.57, 52.16, 65.77, 110.98, 124.38, 125.35,125.41, 125.47, 125.86, 126.49, 126.91, 127.13, 128.21, 128.53, 129.09,129.63, 129.78, 130.19, 130.92, 131.69, 132.27, 133.86, 135.46, 136.46,138.64, 139.00, 139.24, 139.92, 140.24, 140.42, 154.39, 169.58, 173.40.MS (EI): m/z=658 (12), 657 (52), 656 (100), 524 (9), 141 (52), 91 (11),85 (13), 57 (21), 55 (14). MS (FAB+): m/z=658 (14), 657 (49), 656 (100),655 (11), 530 (10), 529 (24), 141 (79). HR-MS (FAB+): Calcd. forC₄₄H₄₈O₅: 656.350175. Found: 656.350400.

3-(4-(Carboxymethoxy)-2,2″-diisobutyl-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionicacid (80)

[0244] To a solution of 36.3 mg (55.26 μmol)3-(2′,2″-Diisobutyl-4-methoxycarbonylmethoxy-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionicacid methyl ester (79) in 8 ml 1.4-dioxane 2.0 ml (16.60 mmol, 301 eq.)25% aq. NaOH-solution and 2.0 ml (3.08 mmol, 56 eq.) 40% aq. solution ofBu₄NOH were added. The resulting mixture was refluxed for 24 h and thencooled to 0° C. Acidification to pH 1 by adding 1 N aq. HCl-solution ledto a white precipitate which was obtained by filtration. A filtrationover silica gel with EtOAc/HOAc (95+5)) as an eluent and a followinglyophilization of the obtained oily product from a solution in CH₃CN andaq. NH₃-solution yielded 36.6 mg (55.2 μmol, 100%) of thebisammonia-salt of3-(4-(Carboxymethoxy)-2,2″-diisobutyl-3-naphthalen-1-ylmethyl-[1,1′:4′,1″]-terphenyl-4″-yl)propionicacid (80) as a white solid. R_(f) (hexanes/EtOAc (1+1), sample dissolvedin HOAc)=0.49. ¹H-NMR (500 MHz, d₄-MeOH): δ=0.43 (d, 6H, J=6.62 Hz,2*CH₃), 0.65 (d, 6H, J=6.62 Hz, 2*CH₃), 1.35 (m, 1H, CH), 1.58 (m, 1H,CH), 2.14 (d, 2H, J=7.41 Hz, CH₂), 2.44 (d, 2H, J=7.25 Hz, CH₂), 2.56(t, 2H, J=7.41 Hz, CH₂CH₂CO₂NH₄), 2.90 (t, 2H, J=7.57 Hz, CH₂CH₂CO₂NH₄),4.58 (s, 2H, CH₂Naphthyl), 4.59 (s, 2H, OCH₂CO₂NH₄), 6.62 (d, 1H, J=2.05Hz), 6.89-7.08 (m, 8H), 7.38-7.45 (m, 4H), 7.73 (m, 1H), 7.83 (m, 1H),8.08 (m, 1H). ¹³C-NMR (125 MHz, d₄-MeOH): δ=22.97, 23.13, 30.75, 31.02,32.69, 33.91, 38.49, 43.45, 43.73, 68.54, 112.71, 126.33, 126.85,126.92, 126.99, 127.26, 128.00, 128.35, 129.01, 129.22, 129.90, 130.84,131.09, 131.41, 131.49, 132.31, 132.42, 134.19, 135.91, 135.95, 138.60,140.16, 140.53, 141.56, 141.86, 142.22, 142.28, 157.00, 177.34, 178.03.MS (FAB−): m/z=629 (18), 628 (29), 627 (54), 570 (42), 569 (100), 568(16), 567 (24), 527 (24), 526 (30), 525 (70), 524 (30), 523 (58), 481(30), 347 (14), 153 (96). HR-MS (FAB−): not possible.

[0245] Synthesis of Piperazine Derivatives Following the Presentation inFIG. 9, Scheme 9, and FIG. 10, Scheme 10

[0246] Synthesis of the Isopropyl-substituted Piperazine Derivative

[0247] Route A

N-Benzyloxycarbonyl-valine-glycine-methylester (82)

[0248] A solution of 2.30 ml (20.92 mmol, 1.06 eq.) 4-methylmorpholinein 2.5 ml EtOAc was added slowly to a suspension of 4.97 g (19.77 mmol)Z-valine (81) in 40 ml EtOAc at −15° C., followed by a solution of 1.90ml (19.87 mmol, 1.01 eq.) ethyl chloroformate in 5 ml EtOAc. Theresulting mixture was stirred for 15 min at −15° C. before a solution of2.30 ml (20.92 mmol, 1.06 eq.) 4-methylmorpholine in 2.5 ml EtOAc,followed by 2.47 g (19.67 mmol, 1.00 eq.) glycinemethylester-hydrochloride were added slowly. After stirring the mixturefor another 60 min. at −15° C. and 12 h at r.t. 20 ml water and 20 mlEtOAc were added. The aq. layer was extracted with EtOAc and the comb.org. fractions were washed successively with sat. aq. NaHCO₃-solution,brine, 2% HCl-solution and brine. After drying the org. layer overNa₂SO₄ and evaporation of the solvent 5.95 g (18.46 mmol, 93.39%)N-Benzyloxycarbonyl-valine-glycine-methylester (82) was obtained as awhite solid.

[0249]¹H-NMR (500 MHz, CDCl₃): δ=0.94 (d, 3H, J=6.94 Hz, CH₃), 0.99 (d,3H, J=6.78 Hz, CH₃), 2.18 (m, 1H, CH, i-prop.), 3.76 (s, 3H, OCH₃),3.99-4.13 (m, 3H, CH and CH₂), 5.11 (m, 2H, CH₂Ph), 5.38 (d, 1H, J=8.20Hz, NH), 6.48 (s, br., 1H, NH), 7.30-7.40 (m, 5H, Ph).

6-(S)-Isopropyl-piperazine-2,5-dione (83)

[0250] Route A:

[0251] 170 mg Pd/C-catalyst and 35 ml (345.53 mmol, 18.91 eq.)cyclohexene were added to a solution of 5.89 g (18.27 mmol)N-Benzyloxycarbonyl-valine-glycine-methylester (82) in 60 ml drymethanol. After refluxing the resulting mixture for 5 h the solvent wasevaporated. The residue was then suspended in 70 ml dry methanol andheated at 65° C. for 110 h. Then the solvent was evaporated, the residuewas dissolved in hot water and filtered through celite. Afterevaporation of the solvent the residue was suspended in 100 ml acetoneand heated at 60° C. for 3 h. Cooling of this solution led to theprecipitation of a white solid, which was filtered and dried in HV. Thisled to 1.43 g (9.13 mmol, 50.00%) 6-(S)-Isopropyl-piperazine-2,5-dione(83) as a white solid.

[0252] Route B:

[0253] A solution of 27.14 g (84.19 mmol)N-Benzyloxycarbonyl-valine-glycine-methylester (82) in 600 ml drymethanol was hydrogenated by adding Pd/C-catalyst and stirring theresulting mixture under H₂ at r.t. for 4 h. After that the mixture wasfiltered through celite and the remaining solution was refluxed for 24h. Evaporation of the solvent yielded 13.17 g (84.33 mmol, 100%)6-(S)-Isopropyl-piperazine-2,5-dione (83) as a white solid.

[0254]¹H-NMR (400 MHz, D₂O): δ=0.56 (d, 3H, J=6.95 Hz, CH₃), 0.65 (d,3H, J=7.07 Hz, CH₃), 1.90 (m, 1H, CH, i-prop.), 3.55 (dt, 1H, X-part ofa ABX-system, J₁=3.66 Hz, J_(AX)=J_(BX)=1.14 Hz, CH, ring), 3.59 (dd,1H, B-part of a ABX-system, J_(AB)=20.00 Hz, J_(BX)=1.14 Hz, CH₂, ring),3.76 (dd, 1H, A-part of a ABX-system, J_(AB)=20.00 Hz, J_(AX)=1.14 Hz,CH₂, ring).

2-(S)-Isopropyl-piperazine (84)

[0255] Route A:

[0256] 203.3 mg (1.30 mmol) 6-(S)-Isopropyl-piperazine-2,5-dione (83)was added by portion to a suspension of 248 mg (6.53 mmol, 5.03 eq.)lithium aluminum hydride in 25 ml dry THF at 0° C. The resulting mixturewas heated at 65° C. for 72 h, then 0.8 ml (6.03 mmol, 4.64 eq.)triethanolamine was added at r.t. and the mixture was stirred foranother hour at r.t. After adding 0.8 ml (44.44 mmol, 34.19 eq.) ofwater and stirring for another 12 h at r.t. the mixture was filtered andevaporated. The resulting oil was dissolved in 10% aq. HCl-solution andwashed with ether. After that the pH of the aq. layer was adjusted to10-12 by adding NaOH-pellets and then the aq. layer was extracted withCH₂Cl₂. The comb. org. fractions were dried over Na₂SO₄ and evaporated.This led to 52.8 mg (0.41 mmol, 31.68%) 2-(S)-Isopropyl-piperazine (84)as colorless crystals.

[0257] Roule B:

[0258] 120 ml (120 mmol, 6.25 eq.) of a 1M solution of BH3*THF in THFwere added via syringe to a suspension of 3.00 g (19.21 mmol)6-(S)-Isopropyl-piperazine-2,5-dione (82) in 100 ml dry THF at r.t.After heating the reaction mixture for 4 h under reflux another 110 ml(110 mmol, 5.73 eq.) of a 1M solution of BH₃*THF in THF were added viasyringe. Then the reaction mixture was refluxed for another 26 h andfiltered after that. Then the solution was cooled in ice and treatedwith ca. 50 ml 30% HBr in HOAc. After stirring the mixture overnight atr.t. the precipitate was collected by filtration and dried under HV.Column chromatography (CH₂Cl₂/MeOH/NH₄OH (16+2+1)) yielded 2.31 g (17.99mmol, 93.65%) 2-(S)-Isopropyl-piperazine (84) as a white solid.

[0259]¹H-NMR (500 MHz, CDCl₃): δ=0.91 (d, 3H, J=6.78 Hz, CH₃), 0.94 (d,3H, J=6.78 Hz, CH₃), 1.53 (m, 1H, CH, i-prop.), 2.33 (m, 1H, CH, ring),2.42 (m, 1H, CH, ring), 2.67-2.82 (m, 2H, CH, ring), 2.89 (m, 1H, CH,ring), 3.01 (m, 2H, CH, ring).

3-(S)-Isopropyl-piperazine-1-carboxylic acid tert-butyl ester (XX)

[0260] Route A:

[0261] 341 mg (2.66 mmol) 2-(S)-Isopropyl-piperazine (84) and 657 mg(2.67 mmol, 1.00 eq.) BOC-ON©(2-(tert-Butoxycarbonyloxyimino)-2-phenylacetonitrile) were dissolved in20 ml 1,4-dioxane and 20 ml water. After adding 2.04 ml (14.64 mmol,5.50 eq.) triethylamine the solution was stirred at r.t. for 24 h. Thenthe mixture was added to water and extracted with EtOAc. The comb. org.fractions were washed with brine, dried over Na₂SO₄ and evaporated.Column chromatography (CH₂Cl₂/MeOH (3+1)) yielded 454.9 mg (1.99 mmol,74.90%) 3-(S)-Isopropyl-piperazine-1-carboxylic acid tert-butyl ester(85) as a clear oil.

[0262] Route B:

[0263] 5.68 ml (14.20 mmol, 1.00 eq.) of a 2.5 N aq. NaOH-solution wereadded to a solution of 1.82 g (14.19 mmol) 2-(S)-Isopropyl-piperazine(82) in 70 ml tert-Butanol and 70 ml H₂O. After cooling to 0° C. 3.10 g(14.20 mmol, 1.00 eq.) Boc-anhydride was added and the mixture wasstirred at 0° C. for 1 h. Then the solution was warmed to r.t. andstirred overnight. After evaporating the tert-Butanol the mixture wasextracted with CH₂Cl₂. The comb. org. fractions were dried over Na₂SO₄and evaporated. Column chromatography (CH₂Cl₂/MeOH (10+1)) yielded 3.19g (13.96 mmol, 98.37%) 3-(S)-Isopropyl-piperazine-1-carboxylic acidtert-butyl ester (85) as a clear oil.

[0264] R_(f) (CH₂Cl₂/MeOH (3+1))=0.71. ¹H-NMR (500 MHz, CDCl₃): δ=0.95(d, 3H, J=6.82 Hz, CH₃), 0.97 (d, 3H, J=6.82 Hz, CH₃), 1.47 (s, 9H,t-Bu), 1.58 (m, 1H, CH, i-prop.), 2.30 (m, 1H, CH, ring), 2.50 (m, 1H,CH, ring), 2.68-2.85 (m, 2H, CH, ring), 2.99 (m, 1H, CH, ring),3.86-4.16 (m, 2H, CH, ring).

[0265] 1.1.1.1 Route B

(S)-4-Isopropyl-oxazolidine-2,5-dione (86)

[0266] 30.4 ml (57.47 mmol, 1.08 eq.) of a 20% solution of phosgene intoluene were added slowly at r.t. to a stirred solution of 6.26 g (53.44mmol) L-valine (81a) in 63 ml dry THF. After the complete addition themixture was heated at 55° C. for 4 h. Then a stream of nitrogen wasbubbled through the solution and passed after that through a 1M aq.NaOH-solution for 20 min. before the solvent was evaporated.Recrystallization of the obtained residue from PE/Ether (2:1) yielded3.62 g (25.29 mmol, 47.32%) (S)-4-Isopropyl-oxazolidine-2,5-dione (86)as a white solid.

[0267]¹H-NMR (500 MHz, CDCl₃): δ=1.03 (d, 3H, J=6.78 Hz, CH₃), 1.09 (d,3H, J=6.94 Hz, CH₃), 2.24 (m, 1H, CH, i-prop.), 4.19 (m, 1H, CH, ring),6.80 (s, br., 1H, NH).

6-(S)-Isopropyl-piperazine-2,5-dione (83)

[0268] 3.10 ml (22.24 mmol, 2.12 eq.) Triethylamine was added to asolution of 1.39 g (11.07 mmol, 1.06 eq.) glycinemethylester-hydrochloride in 13 ml chloroform at −78° C. Then a solutionof 1.50 g (10.48 mmol) (S)-4-Isopropyl-oxazolidine-2,5-dione (86) in 7.7ml dry THF was added under stirring. After stirring for another 4 h at−78° C. the mixture was stored for 12 h at −20° C. before it wasfiltered and the filtrate was evaporated at r.t. The resulting oil wasdissolved in 8 ml THF, filtered again and evaporated. The resultingunstable oil was dissolved in 8 ml toluene and refluxed for 24 h. Thenthe solvent was evaporated and the obtained residue was dissolved in 20ml water and refluxed with decolorising charcoal for 1 h. Afterfiltration through celite 10 ml EtOH were added and the solvent wasevaporated, which led to 338.4 mg (2.17 mmol, 20.68%)6-(S)-Isopropyl-piperazine-2,5-dione (83) as a white powder.

[0269]¹H-NMR (400 MHz, D₂O): δ=0.56 (d, 3H, J=6.95 Hz, CH₃), 0.65 (d,3H, J=7.07 Hz, CH₃), 1.90 (m, 1H, CH, i-prop.), 3.55 (dt, 1H, X-part ofa ABX-system, J₁=3.66 Hz, J_(AX)=J_(BX)=1.14 Hz, CH, ring), 3.59 (dd,1H, B-part of a ABX-system, J_(AB)=20.00 Hz, J_(BX)=1.14 Hz, CH₂, ring),3.76 (dd, 1H, A-part of a ABX-system, J_(AB)=20.00 Hz, J_(AX)=1.14 Hz,CH₂, ring).

[0270] Synthesis of the Benzyl-substituted Piperazine Derivative

N-Benzyloxycarbonyl-phenylalanine-glycine-methylester

[0271] A solution of 7.71 ml (66.82 mmol, 1.05 eq.) 4-methylmorpholinein 13 ml EtOAc was added slowly to a suspension of 20.00 g (66.82 mmol)Z-phenylalanine in 200 ml EtOAc at −15° C., followed by a solution of6.39 ml (70.08 mmol, 1.00 eq.) ethyl chloroformate in 25 ml EtOAc. Theresulting mixture was stirred for 15 min at −15° C. before a solution of7.71 ml (66.82 mmol, 1.05 eq.) 4-methylmorpholine in 13 ml EtOAc,followed by 8.40 g (66.90 mmol, 1.00 eq.) glycinemethylester-hydrochloride were added slowly. After stirring the mixturefor another 60 min at −15° C. and 12 h at r.t. 250 ml water and 200 mlEtOAc were added. The aq. layer was extracted with EtOAc and the comb.org. fractions were washed successively with sat. aq. NaHCO₃-solution,brine, 2% HCl-solution and brine. After drying the org. fractions overNa₂SO₄ and evaporation of the solvent 23.30 g (62.91 mmol, 94.14%)N-Benzyloxycarbonyl-phenylalanine-glycine-methylester was obtained as awhite solid.

[0272] H-NMR (500 MHz, CDCl₃): δ=3.11 (m, 2H, CH₂), 3.74 (s, 3H, OCH₃),3.93 (dd, 1H, B-part of a ABX-system, J_(AB)=20.00 Hz, J_(BX)=6.15 Hz,CH₂), 4.04 (dd, 1H, A-part of a ABX-system, J_(AB)=20.00 Hz, J_(BX)=6.15Hz, CH₂), 4.48 (m, 1H, CH), 5.09 (m, 2H, CH₂Ph), 5.28 (d, 1H, J=6.94 Hz,NH), 6.28 (s, br., 1H, NH), 7.14-7.38 (m, 10H, 2*Ph).

6-(S)-Benzyl-piperazine-2,5-dione

[0273] A solution of 23.30 g (62.91 mmol)N-Benzyloxycarbonyl-phenylalanine-glycine-methylester (obtained above)in 650 ml dry methanol was hydrogenated by adding Pd/C-catalyst andstirring the resulting mixture under H₂ at r.t. for 3 h. After that, themixture was filtered through celite and then half of the solvent wasevaporated. The remaining solution was refluxed for 17 h. Filtration ofthe white precipitate and washing it twice with methanol yielded 10.71 g(52.45 mmol, 83.37%) 6-(S)-Benzyl-piperazine-2,5-dione as a white solid.

[0274]¹H-NMR (500 MHz, d₆-DMSO): δ=2.76 (d, 1H, J=17.34 Hz), 2.89 (dd,1H, J₁=13.56 Hz, J₂=5.04 Hz), 3.09 (dd, 1H, J₁=13.56 Hz, J₂=4.57 Hz),3.36 (dd, 1H, J₁=17.50 Hz, J₂=2.84 Hz), 4.07 (m, 1H), 7.14-7.19 (m, 2H),7.24-7.32 (m, 3H), 7.89 (s, 1H), 8.15 (s, 1H).

2-(S)-Benzyl-piperazine

[0275] 120 ml (120 mmol, 5.93 eq.) of a 1M solution of BH₃*THF in THFwere added via syringe to a suspension of 4.13 g (20.22 mmol)6-(S)-Benzyl-piperazine-2,5-dione (XX) in 100 ml dry THF at r.t.. Afterheating the reaction mixture for 4 h under reflux another 130 ml (130mmol, 6.43 eq.) of a 1M solution of BH3*THF in THF were added viasyringe. Then the reaction mixture was refluxed for another 27 h. Thenthe solution was cooled in ice and treated with 78 ml 30% HBr in HOAc.After stirring the mixture overnight at r.t. the precipitate wascollected by filtration and dried under HV. Column chromatography(CH₂Cl₂/MeOH/NH₄OH (16+2+1)) yielded 2.94 g (16.70 mmol, 82.60%)2-(S)-Benzyl-piperazine as a pale yellow solid.

[0276] R_(f) (CH₂Cl₂/MeOH/NH₄OH (16+2+1))=0.33. ¹H-NMR (500 MHz, CDCl₃):δ=2.47-2.55 (m, 2H), 2.68 (m, 1H), 2.71-2.80 (m, 2H), 2.87 (m, 1H), 2.90(s, 1H), 2.92 (s, 1H), 2.98 (dd, 1H, J₁=11.90 Hz, J₂=2.12 Hz), 7.15-7.22(m, 3H), 7.25-7.30 (m, 2H). MS (EI): m/z=176 (1), 146 (2), 132 (10), 117(6), 92 (12), 91 (18), 85 (100), 65 (5), 56 (23). HR-MS (EI): Calcd. forC₁₁H₁₆N₂: 176.131348. Found: 176.131736.

3-(S)-Benzyl-piperazine-1-carboxylic acid tert-butyl ester

[0277] 6.67 ml (16.68 mmol, 1.00 eq.) of a 2.5 N aq. NaOH-solution wereadded to a solution of 2.94 g (16.68 mmol) 2-(S)-Benzyl-piperazine in 80ml tert-Butanol and 80 ml H₂O. After cooling to 0° C. 3.64 g (16.68mmol, 1.00 eq.) Boc-anhydride was added and the mixture was stirred at0° C. for 2 h. Then the solution was warmed to r.t. and stirredovernight. After evaporating the tert-Butanol the mixture was extractedwith CH₂Cl₂. The comb. org. fractions were dried over Na₂SO₄ andevaporated. Column chromatography (CH₂Cl₂/MeOH (10+1)) yielded 3.82 g(13.82 mmol, 82.87%) 3-(S)-Benzyl-piperazine-1-carboxylic acidtert-butyl ester as a clear oil.

[0278] R_(f) (CH₂Cl₂/MeOH (10+1))=0.45. ¹H-NMR (500 MHz, CDCl₃): δ=1.42(s, 9H, t-Bu), 2.46-2.66 (m, 3H), 2.71-2.94 (m, 4H), 3.45 (s, 1H),3.78-4.16 (m, 2H), 7.13-7.7.22 (m, 3H), Ph—H), 7.24-7.30 (m, 2H,Ph—H).MS (EI): m/z=277 (8, M+H), 185 (30), 129 (100),91 (15), 85 (15),57 (25). HR-MS (EI): Calcd. for C₁₆H₂₅N₂O₂: 277.191603. Found:277.191137

[0279] Synthesis of the Phenyl Compounds

(3-Bromo-phenyl)-phenyl-methanone

[0280] 1.65 ml (12.50 mmol) 3-Bromobenzoyl chloride was dissolved in 10ml of dry benzene. This solution was then added cautiously understirring to a suspension of 2.00 g (15.00 mmol, 1.20 eq.) aluminumchloride in 20 ml dry benzene at 10° C. After the complete addition theresulting mixture was refluxed for 5 h. After quenching the mixture byadding water and conc. hydrochloric acid the aq. layer was extractedwith ethyl acetate. The comb. org. fractions were dried over Na₂SO₄ andevaporated. Column chromatography (hexanes/ether (9+1)) yielded 3.02 g(11.55 mmol, 92.40%) (3-Bromo-phenyl)-phenyl-methanone as a white solid.

[0281] R_(f) (hexanes/ether (9+1))=0.40. ¹H-NMR (500 MHz, CDCl₃): δ=7.37(t, 1H, J=7.88 Hz), 7.51 (m, 2H), 7.62 (tt, 1H, J₁=7.41 Hz, J₂=1.42 Hz),7.72 (m, 2H), 7.79 (m, 2H), 7.94 (t, 1H, J=1.80 Hz).

(3-Bromo-phenyl)-phenyl-methanol

[0282] To a solution of 2.39 g (9.15 mmol)(3-Bromo-phenyl)-phenyl-methanone in 100 ml dry methanol 370 mg (9.78mmol, 1.07 eq.) sodium borohydride was added cautiously at r.t. Afterstirring this solution for 2 h at r.t. the solvent was evaporated andthe residue was taken up in 50 ml water and 50 ml ether. Afterextracting the aq. layer with ether the comb. org. fractions were washedtwice with water, dried over Na₂SO₄ and evaporated. This yielded 2.24 g(8.52 mmol, 93.16%) (3-Bromo-phenyl)-phenyl-methanol as a white solid.

[0283]¹H-NMR (500 MHz, CDCl₃): δ=2.26 (d, 1H, J=3.47 Hz, OH), 5.79 (d,1H, J=3.47 Hz, CH), 7.19 (t, 1H, J=7.88 Hz, Ph—H), 7.27-7.31 (m, 2H,Ph—H), 7.34-7.36 (m, 4H, Ph—H), 7.39 (m, 1H, Ph—H), 7.56 (t, 1H, J=1.89Hz, Ph—H).

1-Benzyl-3-bromo-benzene (87)

[0284] To a suspension of 422 mg (11.12 mmol, 1.31 eq.) lithium aluminumhydride in 30 ml dry ether a solution of 1.38 g (10.35 mmol, 1.22 eq.)aluminum chloride in 18 ml dry ether was added cautiously understirring. After the complete addition the resulting mixture was stirredfor 30 min at r.t. before a solution of 2.24 g (8.52 mmol)(3-Bromo-phenyl)-phenyl-methanol (prepared above) in 19 ml dry ether wasadded dropwise. Then the mixture was refluxed for 12 h and after thatcooled to 0° C. in an ice-bath. After adding cautiously 10 ml of amixture of ether/methanol (1:1) 28 ml 1 N HCl-solution was added and themixture was extracted with ether. The comb. org. fractions were washedwith brine, dried over Na₂SO₄ and evaporated. Column chromatography(PE/CH₂Cl₂ (9+1)) yielded 1.50 g (6.06 mmol, 71.17%)1-Benzyl-3-bromo-benzene (87) as a colorless liquid.

[0285] R_(f) (PE/CH₂Cl₂ (9+1))=0.43. ¹H-NMR (500 MHz, CDCl₃): δ=3.94 (s,2H, CH₂), 7.08-7.23 (m, 5H, Ph—H), 7.25-34 (m, 4H, Ph—H).

4-Iodo-2-isobutylphenol

[0286] 2.43 ml (2.43 mmol, 2.98 eq.) of a 1 M solution of BBr₃ in CH₂Cl₂was added to a solution of 176.0 mg (0.61 mmol) 4-Iodo-2-isobutylanisolein 25 ml dry CH₂Cl₂ at 0° C. via syringe. After that the solution wasstirred for 3 h at 0° C. and then for 12 h at r.t. The reaction mixturewas then added to water and extracted with CH₂Cl₂. The comb. org.fractions were dried over MgSO₄ and evaporated. Column chromatography(hexanes/EtOAc (3+1)) yielded 84.5 mg (0.31 mmol, 50.17%)4-Iodo-2-isobutylphenol as a colorless oil.

[0287] R_(f) (hexanes/EtOAc (3+1))=0.43. ¹H-NMR (500 MHz, CDCl₃): δ=0.89(d, 6H, J=6.57 Hz, 2*CH₃), 1.87 (m, 1H, CH), 2.38 (d, 2H, J=7.33 Hz,CH₂), 4.60 (s, 1H), 6.51 (d, 1H, J=8.21 Hz, 6-Ph—H), 7.30-7.36 (m, 2H,3- and 5-Ph—H). MS (EI): m/z=277 (10), 276 (85), 234 (24), 233 (100),107 (11), 106 (11), 78 (22), 77 (10). HR-MS (EI): Calcd. for C₁₀H₁₃IO:276.0011 17. Found: 276.001260.

Carbonic acid tert-butyl ester 4-iodo-2-isobutyl-phenyl ester

[0288] 80.2 mg (0.29 mmol) 4-Iodo-2-isobutylphenol, 86.0 mg (0.39 mmol,1.36 eq.) Boc-anhydride and 6.0 mg (49 μmol, 0.17 eq.) DMAP weredissolved in 8 ml hexanes and stirred at r.t. for 1.5 h. After addingEtOAc, brine and 1 M aq. HCl-solution the organic layer was washed withaq. NaHCO₃-solution, dried over Na2SO4 and evaporated. Columnchromatography (hexanes/EtOAc (3+1)) yielded 87.9 mg (0.23 mmol, 80.56%)Carbonic acid tert-butyl ester 4-iodo-2-isobutyl-phenyl ester as acolorless oil.

[0289] R_(f) (hexanes/EtOAc (3+1))=0.60. ¹H-NMR (500 MHz, CDCl₃): δ=0.87(d, 6H, J=6.62 Hz, 2*CH₃), 1.51 (s, 9H, t-Bu), 1.83 (m, 1H, CH), 2.35(d, 2H, J=7.25 Hz, CH₂), 6.82 (d, 1H, J=8.04 Hz, 6-Ph—H), 7.46-7.52 (m,2H, 3- and 5-Ph—H). MS (EI): m/z=376 (12), 361 (13), 276 (38), 233 (16),57 (100). HR-MS (EI): Calcd. for C₁₅H₂₁IO₃: 376.053547. Found:376.053399.

(4-Bromo-2-methyl-phenyl)-methanol

[0290] 12.40 ml (12.40 mmol, 1.31 eq.) of a 1M solution of BH₃*THF inTHF were added via syringe to a suspension of 2.04 g (9.49 mmol)4-Bromo-2-methyl-benzoic acid (XX) in 15 ml dry THF at 0° C. After thatthe resulting mixture was slowly warmed to r.t. over a period of 2 h.Then the mixture was quenched by addition of 2.8 ml of 50% aq. THF,dried with Na₂CO₃ over 1 h and evaporated. The residue was dissolved inH₂O and extracted with ether. The comb. org. fractions were washed withH₂O, sat. NaHCO₃-solution and finally with brine. The comb. aq.fractions were back-extracted with ether and washed with sat.NaHCO₃-solution and brine. The comb. org. fractions were dried overNa₂SO₄ and evaporated, which led after drying under high vacuum to 1.80g (8.97 mmol, 94.49%) (4-Bromo-2-methyl-phenyl)-methanol in form of awhite solid.

[0291]¹H-NMR (400 MHz, CDCl₃): δ=2.28 (s, 3H, CH₃), 4.60 (s, 2H, CH₂),7.19 (m, 1H, Ph—H), 7.29 (m, 2H, Ph—H). MS (EI): m/z=202 (77), 201 (15),200 (77), 199 (13), 187 (24), 185 (47), 184 (95), 183 (24), 182 (100),173 (10), 171 (17), 121 (59), 104 (18), 103 (45), 93 (75), 92 (59), 91(84), 90 (20), 89 (21), 78 (33), 77 (85), 65 (23), 63 (34). HR-MS (EI):Calcd. for C₈H₉BrO: 199.983676. Found: 199.984267.

[0292] Coupling Reactions

4-(3′-Benzylphenyl)-3-(S)-isopropyl-piperazine-1-carboxylic acidtert-butyl ester (88)

[0293] Route A:

[0294] 17.9 mg (19.55 μmol, 0.044 eq.) Pd₂(dba)₃ and 5.9 mg (19.38 μmol,0.044 eq.) P(o-tolyl)₃ were dissolved in 6 ml dry toluene. Then 58.9 mg(610 μmol, 1.39 eq.) NaOt-Bu was added, followed by a solution of 101 mg(442 μmol) 3-(S)-Isopropyl-piperazine-1-carboxylic acid tert-butyl ester(85) and 110 mg (445 μmol, 1.01 eq.) 1-Benzyl-3-bromo-benzene (87). Theresulting mixture was heated at 100° C. for 19 h. After filtrating thereaction mixture through celite the solvent was evaporated. Columnchromatography (hexanes/EtOAc (3+1)) yielded 39.6 mg (100 μmol, 22.71%)4-(3′-Benzylphenyl)-3-(S)-iso-propyl-piperazine-1-carboxylic acidtert-butyl ester (88).

[0295] R_(f) (hexanes/EtOAc (3+1))=0.55. ¹H-NMR (500 MHz, CDCl₃): δ=0.79(d, 3H, J=6.78 Hz, CH₃), 0.99 (d, 3H, J=6.62 Hz, CH₃), 1.47 (s, 9H,Ot-Bu), 2.11 (m, 1H, CH in iso-propyl), 2.96-3.14 (m, 2H, ring-CH₂),3.20 (m, 1H, ring-CH), 3.29-3.48 (m, 2H, ring-CH₂), 3.92 (s, 2H,Ph—CH₂), 3.96-4.06 (m, 2H, ring-CH₂), 6.56 (m, 1H, Ph—H), 6.64 (m, 1H,Ph—H), 7.13 (t, 1H, J=7.88 Hz, Ph—H), 7.17-7.23 (m, 3H, Ph—H), 7.29 (m,2H, Ph—H). MS (EI): m/z=394 (6), 351 (15), 296 (15), 295 (72), 272 (16),195 (16), 169 (14), 168 (99), 167 (100), 166 (17), 165 (41), 153 (17),152 (22), 105 (18), 91 (26), 86 (43), 84 (63), 77 (11), 57 (14), HR-MS(EI): Calcd. for C₂₅H₃₄N₂O₂: 394.26203. Found: 394.262138.

[0296] Route B:

[0297] 9.4 mg (10.3 μmol, 0.013 eq.) Pd₂(dba)₃ and 11.4 mg (29.9 μmol,0.04 eq.) 2-Diphenylphosphino-2′-dimethylamino-biphenyl were dissolvedin 6 ml dry toluene. Then 170.7 mg (1.78 mmol, 2.32 eq.) NaOt-Bu wasadded, followed by a solution of 175.0 mg (0.77 mmol)3-(S)-Isopropyl-piperazine-1-carboxylic acid tert-butyl ester (85) and290.6 mg (1.18 μmol, 1.54 eq.) 1-Benzyl-3-bromo-benzene (87). Theresulting mixture was heated at 80° C. for 22 h. After cooling to roomtemperature the mixture was diluted with ether and washed with brine.The comb. org. fractions were dried over Na₂SO₄ and evaporated. Columnchromatography (hexanes/EtOAc (3+1)) yielded 276.5 mg (0.70 mmol,91.49%) 4-(3′-Benzylphenyl)-3-(S)-iso-propyl-piperazine-1-carboxylicacid tert-butyl ester (88).

[0298] R_(f) (hexanes/EtOAc (3+1))=0.55. ¹H-NMR (500 MHz, CDCl₃): δ=0.76(d, 3H, J=6.62 Hz, CH₃), 0.96 (d, 3H, J=6.46 Hz, CH₃), 1.45 (s, 9H,Ot-Bu), 2.09 (m, 1H, CH in iso-propyl), 2.92-3.12 (m, 2H, ring-CH₂),3.16 (m, 1H, ring-CH), 3.25-3.44 (m, 2H, ring-CH₂), 3.90 (s, 2H,Ph—CH₂), 3.92-4.04 (m, 2H, ring-CH₂), 6.54 (m, 1H, Ph—H), 6.59-6.66 (m,2H, Ph—H), 7.10 (t, 1H, J=8.04 Hz, Ph—H), 7.14-7.18 (m, 3H, Ph—H), 7.25(m, 2H, Ph—H).

4-(3′-Benzylphenyl)-3-(S)-isopropyl-piperazine (88a)

[0299] 275.6 mg (0.70 mmol)4-(3′-Benzylphenyl)-3-(S)-iso-propyl-piperazine-1-carboxylic acidtert-butyl ester (88) were dissolved in 8 ml dry CH₂Cl₂ and treated with8 ml TFA, 0.42 ml H₂O and 0.42 ml Et₃SiH. The resulting mixture was thenstirred at r.t. for 3.5 h before it was poured slowly into sat. aq.NaHCO₃-solution. After adding 10% NaOH-solution to the mixture until itbecame alkaline the solution was extracted with CH₂Cl₂. The comb. org.fractions were dried over Na₂SO₄ and evaporated. Column chromatography(CH₂Cl₂/MeOH (4+1)) yielded 191.1 mg (0.65 mmol, 92.92%)4-(3′-Benzylphenyl)-3-(S)-isopropyl-piperazine (88a) as an oil.

[0300] R_(f) (CH₂Cl₂/MeOH (4+1))=0.64. ¹H-NMR (500 MHz, CDCl₃): δ=0.78(d, 3H, J=6.78 Hz, CH₃), 0.90 (d, 3H, J=6.62 Hz, CH₃), 2.31 (m, 1H, CHin iso-propyl), 2.73 (s, br., 1H), 2.89-2.95 (m, 3H), 3.01 (dd, 1H,J₁=12.45 Hz, J₂=3.54 Hz, ring-CH), 3.16 (m, 1H), 3.23 (m, 1H), 3.32 (m,1H), 3.90 (s, 2H, CH₂Ph), 6.56 (m, 1H, Ph—H), 6.65-6.70 (m, 2H, Ph—H),7.11 (t, 1H, J=7.71 Hz, Ph—H), 7.14-7.19 (m, 3H, Ph—H), 7.25 (m, 2H,Ph—H). MS (EI): m/z=294 (7), 252 (21), 251 (100), 222 (5), 196 (10), 165(7), 91 (10), 56 (11). HR-MS (EI): Calcd. for C₂₀H₂₆N₂: 294.209598.Found: 294.210197.

1-(3-Benzyl-phenyl)-2-(S)-isopropyl-4-(2-isopropyl-phenyl)-piperazine(89)

[0301] 110.7 mg (0.38 mmol)4-(3′-Benzylphenyl)-3-(S)-isopropyl-piperazine (88a), 123.5 mg (0.62mmol, 1.65 eq.) 1-Bromo-2-isopropyl-benzene 11.7 mg (12.7 μmol, 0.034eq.) Pd₂(dba)₃, 7.4 mg (19.3 μmol, 0.05 eq.)2-Diphenylphosphino-2′-dimethylamino-biphenyl and 87.3 mg (0.91 mmol,2.42 eq.) NaOt-Bu were dissolved in 5 ml dry toluene. The resultingmixture was heated under N₂ at 80° C. for 15.5 h. After cooling to roomtemperature the mixture was diluted with ether and washed with brine.The comb. org. fractions were dried over Na₂SO₄ and evaporated. Columnchromatography (hexanes/EtOAc (9+1)) yielded 96.5 mg (0.23 mmol, 62.20%)1-(3-Benzyl-phenyl)-2-(S)-isopropyl-4-(2-isopropyl-phenyl)-piperazine(89) as a clear oil.

[0302] R_(f) (hexanes/EtOAc (9+1))=0.44. ¹H-NMR (500 MHz, CDCl₃): δ=0.80(d, 3H, J=6.94 Hz, CH₃), 0.89 (d, 3H, J=6.78 Hz, CH₃), 1.17 (d, 3H,J=6.94 Hz, CH₃), 1.21 (d, 3H, J=6.94 Hz, CH₃), 2.66 (m, 1H, CH, i-prop),2.76-2.90 (m, 2H), 2.93-3.02 (m, 2H), 3.34 (m, 1H, CH, i-prop),3.36-3.52 (m, 2H), 3.61 (m, 1H), 3.91 (s, 2H, CH₂Ph), 6.54 (m, 1H,Ph—H), 6.71 (m, 2H, Ph—H), 7.05-7.20 (m, 7H), 7.24-7.28 (m, 3H, Ph—H).MS (EI): m/z=412 (6, M⁺), 370 (34), 369 (100), 222 (14), 195 (11), 132(10), 91 (11). HR-MS (EI): Calcd. for C₂₉H₃₆N₂: 412.287848. Found:412.288287.

[0303] General Procedure for the Preparation of TerpyridylProteomimetics According to FIG. 19, Scheme 19

[0304] Nicotinoyl chloride hydrochloride (0.3 g, 1.685 mmol), DIEA (0.65g, 5.06 mmol, 3.0 eqv), and ortho- or meta-anisidine (0.21 g, 1.68 mmol,1 eqv) were dissolved in CH2Cl2 and stirred at rt for 48 h. The solutionwas extracted with 1N HCl solution. The aqueous layer was neutralizedwith a NaHCO₃ solution and extracted with CH2Cl2. The organic extractswere combined, dried (MgSO4), filtered, and concentrated in vacuo togive a white solid.

N-(3-methoxyphenyl)nicotinamide; 88% yield

[0305]¹H NMR (400 MHz, CDCl3) d 3.84 (s, 3H), 6.74 (d, J=8.4 Hz, 1H),7.13 (d, J=8.0 Hz, ¹H), 7.27 (t, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.46 (dd,J1=8.4 Hz, J2=7.2 Hz, 1H), 8.03 (s, ¹H), 8.24 (d, J=8.0 Hz, 1H), 8.78(d, J=4.8 Hz, 1H), 9.13 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) d 55.31,106.23, 110.85, 112.61, 123.77, 129.79, 130.95, 135.74, 138.72, 147.62,151.99, 160.18, 163.79; HRMS (EI) Calcd for C13H12N2O2: 228.0899. Found228.0901.

N-(2-methoxyphenyl)nicotinamide; 75% yield

[0306] 1H NMR (400 MHz, CDCl3) d 3.93 (s, 3H), 6.93 (d, J=8.0 Hz, 1H),7.02 (t, J=8.0 Hz, 1H), 7.11 (t, J=7.2 Hz, 1H), 7.44 (dd, J1=8.0 Hz,J2=6.8 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.49 (d, J=8.0 Hz, 1H), 8.55 (s,1H), 8.77 (d, J=5.2 Hz, 1H), 9.12 (s, 1H); 13C NMR (125 MHz, CDCl3) d55.80, 109.96, 119.93, 121.18, 123.64, 124.36, 127.25, 130.97, 135.19,147.88, 148.12, 152.38, 163.21; HRMS (EI) Calcd for C13H12N2O2:228.0899. Found 228.0902.

[0307] Picolinic acid (1.0 g, 8.12 mmol) and (COCl)2 (3.0 g, 24.0 mmol,3 eqv) were dissolved in CH2Cl2 and allowed to stir at rt for 2 h. Thesolvent was evaporated to yield the crude acid chloride. Ortho- ormeta-anisidine (1.0 g, 8.12 mmol, 1.0 eqv) and DIEA (2.1 g, 16.24 mmol,2.0 eqv) were dissolved in CH2Cl2 and added to the acid chloride. Thesolution was stirred at rt for 12 h. The solvent was concentrated invacuo. Column chromatography [Hexanes/EtOAc (1/1)] yielded a whitesolid.

N-(3-methoxyphenyl)-2-pyridinecarboxamide; 83% yield

[0308] 1H NMR (400 MHz, CDCl3) d 3.85 (s, 3H), 6.71 (d, J=9.2 Hz, 1H),7.28 (m, 2H), 7.48 (t, J==7.6 Hz, 1H), 7.58 (s, 1H), 7.91 (t, J=7.6 Hz,1H), 8.30 (d, J=8.8 Hz, 1H), 8.62 (d, J=4.8 Hz, 1H), 10.03 (s, 1H); 13CNMR (125 MHz, CDCl3) d 55.33, 105.12, 110.48, 111.92, 122.38, 126.45,129.72, 137.70, 138.93, 147.94, 149.77, 160.25, 161.96; HRMS (EI) Calcdfor C13H12N2O2: 228.0899. Found 228.0899.

N-(2-methoxyphenyl)-2-pyridinecarboxamide; 89% yield

[0309] 1H NMR (400 MHz, CDCl3) d 3.98 (s, 3H), 6.94 (d, J=6.8 Hz, 1H),7.03 (t, J=7.6 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 7.47 (t, J=5.6 Hz, 1H),7.90 (t, J=7.6 Hz, 1H), 8.30 (d, J=7.6 Hz, 1H), 8.62 (d, J=8.0 Hz, 1H),8.66 (d, J=7.6 Hz, 1H), 10.58 (s, 1H); 13C NMR (125 MHz, CDCl3) d 55.82,110.06, 119.72, 121.03, 122.31, 123.94, 126.19, 127.50, 137.46, 148.15,148.76, 150.33, 161.98; HRMS (EI) Calcd for C13H12N2O2: 228.0899. Found228.0894.

6-Chloro-3-nitro-2-pyridinamine (90a); 89% yield

[0310] 2,6-Dichloro-3-nitropyridine 90 (10.0 g, 51.8 mmol) was dissolvedin 37 ml of a 7N solution of NH₃ in EtOH (0.26 mol, 5.0 eqv) and thesolution was stirred at rt for 24 h. H2O (40 ml) was added and theresulting mixture was filtered to collect the crude yellow product. Thesolid material was dissolved in CH₂Cl₂ and then extracted with a 1N HClsolution. The aqueous extracts were combined and then neutralized withNaHCO₃ before being re-extracted with CH₂Cl₂. The organic fractions werecombined, dried (MgSO₄), filtered, and concentrated in vacuo to yield8.0 g of a yellow solid (89%): ¹H NMR (400 MHz, d₆-DMSO) d 6.77 (d,J=8.8 Hz, 1H), 8.27 (s, 2H), 8.39 (d, J=8.4 Hz, 1H); ¹³C NMR (125 MHz,d₆-DMSO) d 111.89, 126.02, 138.28, 153.36, 154.88; HRMS (EI) Calcd forC₅H₄ClN₃O₂: 172.9997. Found 172.9996.

6-chloro-3-nitro-2(1H)-pyridone (91)

[0311] 6-Chloro-3-nitro-2-pyridinamine (90a) (0.3 g, 1.73 mmol) wasdissolved in 5 ml of conc. H₂SO₄ at 0ø C. A solution of NaNO₂ (0.24 g,3.46 mmol, 2.0 eqv) in 2 ml of H₂O was added cautiously to the arylaminesolution and the mixture was stirred at 0ø C. for 30 min. H₂O (10 ml)was added and the solid precipitate was filtered and washed with coldH₂O several times. The solid was dried under vacuum to give 0.2 g of ayellow solid (67%): ¹H NMR (400 MHz, d6-DMSO) d 7.08 (d, J=6.4 Hz, 1H),8.43 (d, J=6.8 Hz, 1H); 13C NMR (125 MHz, d6-DMSO) d 113.93, 132.10,138.90, 150.27, 156.47; HRMS (EI) Calcd for C5H3ClN2O3: 173.9832. Found173.9830.

[0312] General Procedure for Alkylation of6-chloro-3-nitro-2(1H)-pyridone to Yield Derivatives of Structure 92.

[0313] 6-chloro-3-nitro-2(1H)-pyridone (6-7) (1.34 g, 7.67 mmol), Ag2CO3(1.27 g, 4.61 mmol), and desired electrophile (7.67 mmol, 1.0 eqv) wereadded to 25 ml of toluene. The mixture was stirred at 85ø C. for 18 hand then cooled to rt. The silver salts were filtered off. The filtratewas washed with a NaHCO3 solution and then H2O before being concentratedin vacuo. Column chromatography [Hexanes/EtOAc (5/1)] yielded thealkylated product as yellow/white solid.

6-Chloro-2-methoxy-3-nitropyridine (92a); 86% yield

[0314]¹H NMR (400 MHz, CDC¹³) d 4.14 (s, 3H), 7.05 (d, J=8.4 Hz, 1H),8.28 (d, J=8.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 55.62, 116.63,132.36, 137.52, 152.99, 156.33; HRMS (EI) Calcd for C6H5ClN2O3:187.9983. Found 187.9983.

6-Chloro-2-isopropoxy-3-nitropyridine (92b); 81% yield

[0315]¹H NMR (400 MHz, CDCl3) d 1.43 (d, J=6.0 Hz, 6H), 5.50 (m, 1H),6.97 (d, J=8.0 Hz, 1H), 8.21 (d, J=8.4 Hz, 1H); 13C NMR (125 MHz, CDCl3)d 21.71, 72.49, 115.87, 132.68, 137.32, 152.73, 155.73; HRMS (EI) Calcdfor C8H9ClN2O3: 216.0302. Found 216.0298.

2-(Benzyloxy)-6-chloro-3-nitropyridine (92c); 47% yield

[0316]¹H NMR (400 MHz, CDCl3) d 5.57 (s, 2H), 7.04 (d, J=8.0 Hz, 1H),7.35 (m, 3H), 7.52 (d, J=8.0 Hz, 2H), 8.27 (d, J=8.0 Hz, 1H); 13C NMR(125 MHz, CDCl3) d 69.67, 116.72, 127.75, 128.14, 128.41, 132.26,135.05, 137.51, 152.62, 155.45; HRMS (FAB) Calcd for C12H10ClN2O3:265.0379. Found 265.0379.

[0317] General Procedure for Conversion of Aryl Chlorides (92) to ArylCarboxylic Acids (93).

[0318] The aryl chloride (92) (4.2 mmol), vinyltributyltin (4.6 mmol,1.1 eqv), and Pd(PPh3)4 (5 mol %) were dissolved in toluene and reluxedfor 18 h. The solvent was removed in vacuo, H₂O was added, and themixture was extracted with CH₂Cl₂. The organic fractions were combined,dried (MgSO4), filtered, and concentrated in vacuo to give the crudeolefin as a dark oil. The olefin was dissolved in 20 ml of CH₂Cl₂ and0.5 ml of AcOH at −78ø C. Ozone was bubbled through the solution for 1 hor until the solution turned blue. The solution was neutralized withNaHCO₃ (aq) before being extracted with CH₂Cl₂. The organic fractionswere combined, dried (MgSO4), filtered, and concentrated in vacuo togive the crude aldehyde as a yellow solid/oil. The crude material wasdissolved in 40 ml of EtOH. To this solution was added AgNO3 (10.4 mmol,2.5 eqv) in 7.0 ml of H2O. A solution of NaOH (83.8 mmol, 20.0 eqv) in60.0 ml of H2O was added dropwise over 1 h. The resulting mixture wasallowed to stir for 2 h at rt before being filtered. The filtrate wasextracted with CH2Cl2 and the organic fractions were discarded. Theaqueous layer was acidified to pH 3.0 using 1N HCl and re-extracted withCH2Cl2. The organic fractions were combined, dried (MgSO4), filtered,and concentrated in vacuo to give the aryl carboxylic acid as a whitesolid.

6-Methoxy-5-nitro-2-pyridinecarboxylic acid (93a); 76% yield

[0319] 1H NMR (400 MHz, CDCl3) d 4.22 (s, 3H), 7.97 (d, J=8.0 Hz, 1H),8.43 (d, J=8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 55.52, 117.34,136.98, 137.28, 146.47, 155.84, 162.08; HRMS (EI) Calcd for C7H6N2O5:198.0277. Found 198.0282.

6-Isopropoxy-5-nitro-2-pyridinecarboxylic acid (93b); 76% yield

[0320] 1H NMR (400 MHz, CDCl3) d 1.48 (d, J=6.0 Hz, 6H), 5.50 (m, 1H),7.91 (d, J=8.0 Hz, 1H), 8.36 (d, J=8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)d 21.69, 72.69, 116.64, 136.61, 137.68, 146.29, 155.06, 162.54; HRMS(EI) Calcd for C9H10N2O5: 227.0668. Found 227.0668.

6-(Benzyloxy)-5-nitro-2-pyridinecarboxylic acid (93c); 70% yield

[0321] 1H NMR (400 MHz, CDCl3) d 5.62 (s, 2H), 7.39 (m, 3H), 7.49 (m,2H), 7.92 (d, J=8.0 Hz, 1H), 8.37 (d, J=8.0 Hz, 1H); 13C NMR (125 MHz,CDCl3) d 69.90, 118.00, 127.69, 128.48, 128.70, 134.99, 136.56, 136.98,146.84, 155.18, 164.62; HRMS (FAB) Calcd for C13H11N2O5: 275.0668. Found275.0668.

[0322] General Procedure for the Synthesis of Methyl Esters (93e).

[0323] The aryl carboxylic acid (6-9a) (2.22 mmol), and a catalyticamount of p-toluenesulfonic acid (50 mg) were dissolved in 10 ml ofanhydrous MeOH. The solution was stirred at 55ø C. for 48 h. Thereaction mixture was cooled to rt and concentrated in vacuo. Columnchromatography [Hexanes/EtOAc (2/1)] yielded the methyl ester as a whitesolid.

Methyl 6-methoxy-5-nitro-2-pyridinecarboxylate (93e1); 87% yield

[0324] 1H NMR (400 MHz, CDCl3) d 4.00 (s, 3H), 4.19 (s, 3H), 7.80 (d,J=8.0 Hz, 1H); 8.32 (d, J=8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 53.20,55.22, 117.97, 135.69, 136.14, 148.71, 156.07, 163.76; HRMS (EI) Calcdfor C8H8N2O5: 212.0433. Found 212.0431.

Methyl 6-isopropoxy-5-nitro-2-pyridinecarboxylate (93e2); 92% yield

[0325] 1H NMR (400 MHz, CDCl3) d 1.43 (d, J=6.4 Hz, 6H), 3.99 (s, 3H),5.63 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 8.24 (d, J=8.0 Hz, 1H); 13C NMR(125 MHz, CDCl3) d 21.73, 53.09, 71.82, 117.22, 135.33, 136.47, 148.54,155.39, 163.96; HRMS (EI) Calcd for C10H12N2O5: 241.0824. Found241.0823.

Methyl 6-(benzyloxy)-5-nitro-2-pyridinecarboxylate (93e3); 89% yield

[0326] 1H NMR (400 MHz, CDCl3) d 4.01 (s, 3H), 5.65 (s, 2H), 7.37 (m,3H), 7.55 (d, J=7.2 Hz, 2H), 7.79 (d, J=8.0 Hz, 1H), 8.30 (d, J=8.0 Hz,1H); 13C NMR (125 MHz, CDCl3) d 53.15, 69.38, 118.09, 128.22, 128.24,128.44, 135.44, 135.77, 136.10, 148.45, 155.33, 163.65; HRMS (EI) Calcdfor C14H12N2O5: 287.0668. Found 287.0666.

[0327] General Procedure for the Reduction of Arylnitro Derivatives 93,96, and 96b to Yield Aryl Amines 94, 95, and 97.

[0328] The arylnitro compound (1.2 mmol) and 10% Pd/C (50 mg) were addedto 12 ml of MeOH. (PtO2 and THF solvent were used with compoundspossessing a benzyloxy side chain.) The mixture was stirred at rt for 10h under 1 atm of H2. The reaction mixture was filtered through celiteand then concentrated. Column chromatography [Hexanes/EtOAc (3/1)]yielded the arylamine as a white solid.

Methyl 5-amino-6-methoxy-2-pyridinecarboxylate (94a); 81% yield

[0329] 1H NMR (400 MHz, CDCl3) d 3.91 (s, 3H), 4.08 (s, 3H), 4.23 (s,2H), 6.85 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H); 13C NMR (125 MHz,CDCl3) d 52.14, 53.58, 117.88, 121.25, 132.92, 135.09, 151.62, 165.92;HRMS (EI) Calcd for C8H10N2O3: 182.0691. Found 182.0691.

Methyl 5-amino-6-isopropoxy-2-pyridinecarboxylate (94b); 91% yield

[0330] 1H NMR (400 MHz, CDCl3) d 1.37 (d, J=4.4 Hz, 6H), 3.89 (s, 3H),5.52 (m, 1H), 6.86 (d, J=6.0 Hz, 1H), 7.61 (d, J=6.4 Hz, 1H); 13C NMR(125 MHz, CDCl3) d 22.13, 52.03, 68.65, 117.98, 120.63, 133.10, 135.08,150.85, 166.04; HRMS (EI) Calcd for C10H14N2O3: 211.1083. Found211.1084.

Methyl 5-amino-6-(benzyloxy)-2-pyridinecarboxylate (94c); 63% yield

[0331] 1H NMR (400 MHz, CDCl3) d 3.91 (s, 3H), 4.36 (s, 2H), 5.48 (s,2H), 6.84 (d, J=8.0 Hz, 1H), 7.36 (m, 3H), 7.47 (d, J=8.0 Hz, 1H), 7.65(d, J=7.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 52.04, 67.90, 117.90,121.42, 127.93, 128.33, 128.42, 132.33, 135.21, 136.86, 150.86, 165.85;HRMS (EI) Calcd for C14H14N2O3: 258.1004. Found 258.1003.

Methyl5-{[(5-amino-6-methoxy-2-pyridinyl)carbonyl]amino}-6-methoxy-2-pyridinecarboxylate(96a); 100% yield

[0332] 1H NMR (400 MHz, CDCl3) d 3.95 (s, 3H), 4.12 (s, 3H), 4.16 (s,3H), 4.18 (s, 2H), 6.96 (d, J=7.2 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.82(d, J=8.0 Hz, 1H), 8.87 (d, J=8.4 Hz, 1H), 10.39 (s, 1H); 13C NMR (125MHz, CDCl3) d 52.41, 53.33, 54.25, 118.16,119.05, 120.66, 124.58,126.94, 134.65, 135.04, 137.45, 150.58, 152.81, 163.45, 165.48; HRMS(EI) Calcd for C15H16N4O5: 332.1120. Found 332.1119.

Methyl5-{[(5-amino-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinecarboxylate(96b); 87% yield

[0333] 1H NMR (400 MHz, CDCl3) d 1.43 (d, J=6.0 Hz, 6H), 1.46 (d, J=6.4Hz, 6H), 3.93 (s, 3H), 4.26 (s, 2H), 5.54 (m, 1H), 5.65 (m, 1H), 6.95(d, J=7.6 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 8.90(d, J=8.0 Hz, 1H), 10.25 (s, 1H); 13C NMR (125 MHz, CDCl3) d 22.13,22.16, 52.30, 68.57, 69.26, 117.72, 118.99, 120.04, 124.68, 127.03,134.66, 135.25, 137.44, 149.69, 151.91, 163.61, 165.58; HRMS (EI) Calcdfor C19H24N4O5: 389.1825. Found 389.1825.

Methyl5-{[(5-amino-6-(benzyloxy)-2-pyridinyl)carbonyl]amino}-6-(benzyloxy)-2-pyridinecarboxylate(96c); 76% yield

[0334] 1H NMR (400 MHz, CDCl3) d 3.96 (s, 3H), 4.28 (s, 2H), 4.97 (s,2H), 5.55 (s, 2H), 6.91 (d, J=7.6 Hz, 1H), 7.03 (t, J=7.6 Hz, 1H), 7.13(t, J=7.2 Hz, 2H), 7.25 (m, 2H), 7.33 (m, 3H), 7.43 (d, J=7.2 Hz, 2H),7.74 (d, J=7.6 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 8.95 (d, J=8.4 Hz, 1H),10.27 (s, 1H); 13C NMR (125 MHz, CDCl3) d 52.40, 67.72, 68.89, 118.36,118.91, 120.72, 124.93, 126.83, 128.14, 128.26, 128.29, 128.30, 128.41,128.71, 134.14, 135.18, 136.10, 136.39, 137.25, 149.78, 152.25, 163.46,165.38; HRMS (FAB) Calcd for C27H25N4O5: 485.1825. Found 485.1826.

Methyl5-{[(5-amino-6-(benzyloxy)-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinecarboxylate(96d); 76% yield

[0335] 1H NMR (400 MHz, CDCl3) d 1.38 (d, J=6.4 Hz, 6H), 3.92 (s, 3H),4.39 (s, 2H), 5.53 (s, 2H), 5.58 (m, 1H), 6.97 (d, J=7.6 Hz, 1H), 7.41(m, 3H), 7.50 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.0 Hz, 1H), 8.89 (d, J=8.0Hz, 1H), 10.38 (s, 1H); 13C NMR (125 MHz, CDCl3) d 22.12, 52.27, 67.97,69.42, 118.33, 119.07, 119.99, 124.36, 126.92, 128.32, 128.34, 128.60,134.21, 135.14, 136.24, 137.31, 149.81, 151.82, 163.31, 165.51; HRMS(FAB) Calcd for C23H25N4O5: 437.1825. Found 437.1824.

Methyl5-{[(5-{[(5-amino-6-methoxy-2-pyridinyl)carbonyl]amino}-6-methoxy-2-pyridinyl)carbonyl]amino}-6-methoxy-2-pyridinecarboxylate(97a); 96% yield

[0336] 1H NMR (500 MHz, CD2Cl2) d 3.89 (s, 3H), 4.12 (s, 3H), 4.13 (s,3H), 4.19 (s, 3H), 4.33 (s, 2H), 8.96 (d, J=8.0 Hz, 1H), 7.69 (d, J=7.5Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 8.84 (d, J=8.0Hz, 1H), 8.93 (d, J=8.0 Hz, 1H), 10.34 (s, 1H), 10.40 (s, 1H); 13C NMR(125 MHz, CD2Cl2) d 52.54, 53.72, 54.40, 54.50, 117.72, 118.36, 119.19,120.73, 124.94, 125.65, 127.03, 127.53, 134.77, 135.78, 138.29, 139.19,151.03, 152.33, 153.30, 163.02, 163.54, 165.53; HRMS (FAB) Submitted.

Methyl5-{[(5-{[(5-amino-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinecarboxylate(97b); 99% yield

[0337] 1H NMR (400 MHz, CDCl3) d 1.45 (d, J=6.0 Hz, 6H), 1.49 (d, J=6.4Hz, 6H), 1.53 (d, J=6.4 Hz, 6H), 3.94 (s, 3H), 5.55 (m, 1H), 5.67 (m,1H), 6.98 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz,1H), 7.93 (d, J=8.4 Hz, 1H), 8.93 (d, J=8.4 Hz, 1H), 9.02 (d, J=8.4 Hz,1H), 10.25 (s, 1H), 10.30 (s, 1H); 13C NMR (125 MHz, CDCl3) d 22.18,22.18, 22.18, 52.36, 68.58, 69.24, 69.36, 117.35, 117.86, 119.06,120.04, 125.02, 125.84, 126.70, 127.18, 134.60, 135.29, 137.85, 138.86,149.68, 150.85, 151.96, 162.94, 163.50, 165.51; HRMS (EI) Calcd forC28H34N6O7: 566.2489. Found 566.2489.

Methyl5-{[(5-{[(5-amino-6-(benzyloxy)-2-pyridinyl)carbonyl]amino}-6-(benzyloxy)-2-pyridinyl)carbonyl]amino}-6-(benzyloxy)-2-pyridinecarboxylate(97c); 61% yield

[0338] 1H NMR (400 MHz, d6-DMSO) d 3.90 (s, 3H), 5.16 (s, 2H), 5.31 (s,2H), 5.57 (s, 2H), 5.64 (s, 2H), 7.04 (d, J=7.6 Hz, 1H), 7.14 (m, 5H),7.34 (m, 8H), 7.49 (d, J=6.8 Hz, 2H), 7.62 (d, J=7.6 Hz, 1H), 7.82 (d,J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 8.83 (d, J=8.0 Hz, 1H), 8.90 (d,J=8.4 Hz, 1H), 10.09 (s, 1H), 10.22 (s, 1H); HRMS (FAB) Calcd forC40H35N6O7: 711.2567. Found 711.2569.

Methyl5-{[(5-{[(5-amino-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-(benzyloxy)-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinecarboxylate(97d); 66% yield

[0339] 1H NMR (400 MHz, CDCl3) d 1.11 (d, J=5.6 Hz, 6H), 1.36 (d, J=6.0Hz, 6H), 3.93 (s, 3H), 4.19 (s, 2H), 4.91 (m, 1H), 5.60 (m, 1H), 5.64(s, 2H), 6.91 (d, J=8.0 Hz, 1H), 7.42 (m, 5H), 7.72 (d, J=8.0 Hz, 1H),7.79 (d, J=8.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 8.91 (d, J=8.0 Hz, 1H),9.10 (d, J=8.4 Hz, 1H), 10.18 (s, 1H), 10.43 (s, 1H); 13C NMR (125 MHz,CDCl3) d 21.79, 22.20, 52.20, 68.90, 69.17, 69.68, 117.86, 117.99,118.88, 119.99, 124.93, 126.37, 126.72, 127.15, 128.71, 128.74, 128.87,134.65, 135.42, 136.09, 138.11, 138.97, 149.89, 151.39, 152.08, 162.69,163.61, 165.47; HRMS (FAB) Calcd for C32H35N6O7: 615.2567. Found615.2570.

Methyl5-{[(5-{[(5-amino-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-(benzyloxy)-2-pyridinyl)carbonyl]amino}-6-(benzyloxy)-2-pyridinecarboxylate(97e); 52% yield

[0340] 1H NMR (400 MHz, CDCl3) d 1.09 (d, J=6.0 Hz, 6H), 3.96 (s, 3H),4.22 (s, 2H), 4.82 (m, 1H), 5.05 (s, 2H), 5.55 (s, 2H), 6.86 (d, J=7.6Hz, 1H), 7.01 (t, J=7.2 Hz, 1H), 7.09 (t, J=7.2 Hz, 2H), 7.30 (m, 2H),7.40 (m, 5H), 7.67 (d, J=8.0 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.93 (d,J=8.0 Hz, 1H), 8.96 (d, J=8.0 Hz, 1H), 9.04 (d, J=8.0 Hz, 1H), 10.04 (s,1H), 10.25 (s, 1H); 13C NMR (125 MHz, CDCl3) d 21.70, 52.45, 68.51,68.96, 68.97, 117.72, 117.87, 118.61, 120.66, 125.27, 125.92, 125.93,126.47, 127.01, 128.25, 128.39, 128.52, 128.74, 129.18, 134.18, 135.31,135.97, 136.04, 137.67, 138.50, 149.62, 151.13, 152.29, 162.77, 163.55,165.30; HRMS (FAB) Calcd for C36H35N6O7: 663.2567. Found 663.2569.

[0341] General Procedure for Coupling Aryl Acid Chlorides (95) and ArylAmines (94 and 96a) to Yield Dimer (96) and Trimer Structures

[0342] The aryl carboxylic acid (0.44 mmol), (COCl)2 (8.8 mmol, 20 eqv),and DMF (cat.) were dissolved in 5 ml of CH2Cl2. The solution wasallowed to stir for 2 h at rt and was then concentrated in vacuo. Asolution of the aryl amine (0.44 mmol, 1.0 eqv) and DIEA (1.33 mmol, 3.0eqv) in 5 ml of CH2Cl2 was added to the crude acid chloride. Thesolution was stirred for 12 h at rt and was then concentrated in vacuo.Column chromatography [Hexanes/EtOAc (2/1)] yielded the arylamide as awhite/yellow solid.

Methyl6-methoxy-5-{[(6-methoxy-5-nitro-2-pyridinyl)carbonyl]amino}-2-pyridinecarboxylate;98% yield

[0343] 1H NMR (400 MHz, CDCl3) d 3.97 (s, 3H), 4.18 (s, 3H), 4.28 (s,3H), 7.85 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 8.46 (d, J=8.0 Hz,1H), 8.86 (d, J=8.0 Hz, 1H), 10.37 (s, 1H); 13C NMR (125 MHz, CDCl3) d52.57, 54.53, 54.95, 115.70, 120.43, 125.54, 125.57, 136.36, 136.92,139.04, 149.80, 152.90, 155.51, 160.44, 165.16; HRMS (EI) Calcd forC15H14N4O7: 362.0862. Found 362.0854.

Methyl6-isopropoxy-5-{[(6-isopropoxy-5-nitro-2-pyridinyl)carbonyl]amino}-2-pyridinecarboxylate;76% yield

[0344] 1H NMR (400 MHz, CDCl3) d 1.44 (d, J=6.0 Hz, 6H), 1.53 (d, J=6.0Hz, 6H), 3.95 (s, 3H), 5.67 (m, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.96 (d,J=8.0 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.89 (d, J=8.0 Hz, 1H), 10.22 (s,1H); 13C NMR (125 MHz, CDCl3) d 21.82, 22.14, 52.46, 69.76, 71.70,115.10, 119.81, 125.65, 125.65, 136.53, 136.79, 138.99, 149.71, 152.06,154.73, 160.71, 165.28; HRMS (FAB) Calcd for C19H23N4O7: 419.1567. Found419.1569.

Methyl6-(benzyloxy)-5-{[(6-(benzyloxy)-5-nitro-2-pyridinyl)carbonyl]amino}-2-pyridinecarboxylate;82% yield

[0345] 1H NMR (400 MHz, CDCl3) d 4.04 (s, 3H), 5.17 (s, 2H), 5.65 (s,2H), 7.28 (m, 5H), 7.36 (m, 3H), 7.51 (d, J=7.2 Hz, 2H), 7.93 (d, J=8.4Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 8.43 (d, J=7.6 Hz, 1H), 8.97 (d, J=8.4Hz, 1H), 10.30 (s, 1H); 13C NMR (125 MHz, CDCl3) d 52.56, 69.16,69.35,115.74, 120.50, 125.46, 125.91, 128.15, 128.44, 128.45, 128.62, 128.63,128.94, 134.82, 135.78, 136.48, 136.71, 138.88, 149.45, 152.42, 154.69,160.48, 165.05; HRMS (FAB) Calcd for C27H23N4O7: 515.1567. Found515.1567.

Methyl5-({[(6-(benzyloxy)-5-nitro-2-pyridinyl]carbonyl}amino)-6-isopropoxy-2-pyridinecarboxylate;78% yield

[0346] 1H NMR (400 MHz, CDCl3) d 1.44 (d, J=6.0 Hz, 6H), 3.95 (s, 3H),5.65 (m, 1H), 5.70 (s, 2H), 7.42 (m, 3H), 7.55 (d, J=6.8 Hz, 2H), 7.81(d, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 8.45 (d, J=8.0 Hz, 1H), 8.88(d, J=8.0 Hz, 1H), 10.35 (s, 1H); 13C NMR (125 MHz, CDCl3) d 22.22,52.46, 69.48, 70.03, 115.91, 119.79, 125.55, 125.56, 127.84, 128.66,128.80, 134.68, 136.42, 136.89, 139.03, 149.75, 152.04, 154.84, 160.37,165.22; HRMS (FAB) Calcd for C23H23N4O7: 467.1566. Found 467.1566.

Methyl6-methoxy-5-{[(6-methoxy-5-{[(6-methoxy-5-nitro-2-pyridinyl)carbonyl]amino}-2-pyridinyl)carbonyl]amino}-2-pyridinecarboxylate;97% yield

[0347] 1H NMR (400 MHz, CDCl3, 50ø C.) d 3.96 (s, 3H), 4.19 (s, 3H),4.25 (s, 3H), 4.30 (s, 3H), 7.84 (d, J=8.4 Hz, 1H), 8.02 (dd, J1=8.0 Hz,J2=7.6 Hz, 2H), 8.44 (d, J=7.6 Hz, 1H), 8.89 (d, J=8.4 Hz, 1H), 8.98 (d,J=8.0 Hz, 1H), 10.31 (s, 1H), 10.36 (s, 1H); HRMS (EI) Calcd forC22H20N6O9: 512.1292. Found 512.1294.

Methyl6-isopropoxy-5-{[-(6-isopropoxy-5-{[(6-isopropoxy-5-nitro-2-pyridinyl)carbonyl]amino}-2-pyridinyl)carbonyl]amino}-2-pyridinecarboxylate;79% yield

[0348] 1H NMR (500 MHz, CDCl3) d 1.45 (d, J=6.0 Hz, 6H), 1.53 (d, J=6.5Hz, 6H), 1.55 (d, J=6.5 Hz, 6H), 3.95 (s, 3H), 5.69 (m, 1H), 7.80 (d,J=8.0 Hz, 1H), 7.98 (dd, J1=8.0 Hz, J2=8.0 Hz, 2H), 8.39 (d, J=8.0 Hz,1H), 8.92 (d, J=8.0 Hz, 1H), 9.02 (d, J=8.5 Hz, 1H), 10.21 (s, 1H),10.27 (s, 1H); 13C NMR (125 MHz, CDCl3) d 21.86, 22.19, 22.19, 52.34,69.44, 69.76, 71.68, 115.23, 117.24, 120.01, 125.17, 125.83, 126.45,126.85, 136.57, 136.87, 138.14, 140.39, 149.61, 151.06, 151.96, 154.74,160.62, 162.51, 165.44; HRMS (FAB) Calcd for C28H33N6O9: 597.2309. Found597.2312.

Methyl6-(benzyloxy)-5-{[(6-(benzyloxy)-5-{[(6-(benzyloxy)-5-nitro-2-pyridinyl)carbonyl]amino}-2-pyridinyl)carbonyl]amino}-2-pyridinecarboxylate;69% yield

[0349] 1H NMR (400 MHz, CDCl3) d 3.96 (s, 3H), 5.09 (s, 3H), 5.56 (s,2H), 6.97 (t, J=7.6 Hz, 1H), 7.07 (t, J=7.2 Hz, 2H), 7.17 (m, 3H), 7.25(m, 4H), 7.33 (m, 3H), 7.40 (d, J=7.6 Hz, 2H), 7.85 (d, J=8.0 Hz, 1H),7.95 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H),8.97 (d, J=8.4 Hz, 1H), 9.00 (d, J=8.0 Hz, 1H), 10.11 (s, 1H), 10.23 (s,1H); 13C NMR (125 MHz, CDCl3) d 52.41, 69.15, 69.20, 69.25, 115.90,117.88, 120.67, 125.54, 125.72, 126.34, 127.06, 128.36, 128.36, 128.48,128.56, 128.58, 128.67, 128.81, 128.90, 129.20, 134.96, 135.42, 136.19,136.74, 136.62, 138.23, 140.39, 149.50, 151.59, 152.44, 154.79, 160.47,162.42, 165.28; HRMS (FAB) Calcd for C40H33N6O9: 741.2309. Found741.2308.

Methyl5-{[(6-(benzyloxy)-5-{[(6-isopropoxy-5-nitro-2-pyridinyl)carbonyl]amino}-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinecarboxylate; 84% yield

[0350] 1H NMR (400 MHz, CDCl3) d 1.12 (d, J=6.0 Hz, 6H), 1.35 (d, J=6.4Hz, 6H), 3.93 (s, 3H), 4.97 (m, 1H), 5.58 (m, 1H), 5.63 (s, 2H), 7.45(m, 3H), 7.52 (m, 2H), 7.79 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H),8.03 (d, J=8.0 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.90 (d, J=8.0 Hz, 1H),9.08 (d, J=8.0 Hz, 1H), 10.14 (s, 1H), 10.45 (s, 1H); 13C NMR (125 MHz,CDCl3) d 21.38, 22.16, 52.32, 69.26, 69.71, 72.26, 115.08, 117.79,119.97, 124.94, 125.69, 126.40, 127.18, 128.84, 129.02, 129.06, 135.52,136.31, 136.91, 138.23, 140.33, 149.39, 151.51, 151.99, 154.77, 160.76,162.22, 165.40; HRMS (FAB) Calcd for C32H33N6O9: 645.2309. Found645.2309.

Methyl6-(benzyloxy)-5-{[(6-(benzyloxy)-5-{[(6-isopropoxy-5-nitro-2-pyridinyl)carbonyl]amino}-2-pyridinyl)carbonyl]amino}-2-pyridinecarboxylate;79% yield

[0351] 1H NMR (400 MHz, CDCl3) d 1.15 (d, J=6.0 Hz, 6H), 3.97 (s, 3H),4.96 (m, 1H), 5.10 (s, 2H), 5.56 (s, 2H), 7.02 (t, J=7.6 Hz, 1H), 7.09(t, J=6.8 Hz, 2H), 7.31 (m, 2H), 7.42 (m, 5H), 7.84 (d, J=8.0 Hz, 1H),7.91 (d, J=8.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 8.29 (d, J=8.0 Hz, 1H),8.96 (d, J=8.0 Hz, 1H), 9.03 (d, J=8.0 Hz, 1H), 10.01 (s, 1H), 10.24 (s,1H); 13C NMR (125 MHz, CDCl3) d 21.44, 52.39, 68.96, 69.06, 72.21,115.10, 117.83, 120.62, 125.53, 125.76, 126.31, 127.10, 128.30, 128.44,128.74, 128.76, 128.89, 129.24, 135.72, 136.22, 136.94, 138.18, 140.24,146.52, 149.40, 151.50, 152.39, 154.76, 160.76, 162.39, 165.23; HRMS(FAB) Calcd for C36H33N6O9: 693.2309. Found 693.2308.

5-{[(5-{[(5-amino-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinecarboxylicacid

[0352] Methyl5-{[(5-{[(5-amino-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinecarboxylate(6-1b) (15.0 mg, 0.026 mmol) was dissolved in 3 ml of dioxane. NaOH(0.15 ml of a 1 N solution) was added and the resulting mixture wasstirred for 20 h at rt. The reaction was acidified with 1N HCl to pH 1.0and then extracted with CH2Cl2. The organic fractions were combined,dried (MgSO4), filtered, and concentrated in vacuo. The crude productwas washed several times with hexanes to yield 11.2 mg of a white solid(78%): 1H NMR (500 MHz, CDCl3) d 1.49 (d, J=6.0 Hz, 6H), 1.50 (d, J=6.5Hz, 6H), 1.53 (d, J=6.5 Hz, 6H), 5.48 (m, 1H), 5.54 (m, 1H), 5.65 (m,1H), 6.99 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.93 (d, J=8.0 Hz,1H), 7.95 (d, J=8.0 Hz, 1H), 9.04 (d, J=8.0 Hz, 1H), 9.08 (d, J=8.0 Hz,1H), 10.25 (s, 1H), 10.30 (s, 1H); 13C NMR (125 MHz, CDCl3) d 22.08,22.17, 22.20, 68.59, 69.25, 70.30, 117.62, 117.90, 118.92, 120.04,125.87, 126.37, 127.43, 128.02, 134.61, 135.57, 138.07, 138.49, 149.72,150.86, 151.14, 162.91, 163.49, 163.72; HRMS (FAB) Calcd for C27H33N6O7:553.2411. Found 553.2411.

Methyl5-{[(5-{[(5-{[(5-amino-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinecarboxylate

[0353] 6-Isopropoxy-5-nitro-2-pyridinecarboxylic acid (24.0 mg, 0.105mmol), (COCl)2 (0.268 g, 2.12 mmol, 20 eqv), and DMF (cat.) weredissolved in 3 ml of CH2Cl2. The solution was allowed to stir for 2 h atrt and was then concentrated in vacuo. A solution of Methyl5-{[(5-{[(5-amino-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinecarboxylate(6-1b) (30.0 mg, 0.052 mmol, 0.5 eqv) and DIEA (27.3 mg, 0.21 mmol, 2.0eqv) in 3 ml of CH2Cl2 was added to the crude acid chloride. Thesolution was stirred for 12 h at rt. The precipitate was filtered, andwashed several times with cold CH2Cl2. The nitro-derivative and 10% Pd/C(5 mg) were added to 5 ml of 1:1 MeOH/CH2Cl2 and the suspension wasstirred for 20 min at rt under 1 atm H2. The solution was filteredthrough celite and the filtrate was concentrated in vacuo to give 36 mgof a white solid (92%): 1H NMR (500 MHz, CDCl3) d 1.45 (d, J=6.5 Hz,6H), 1.50 (d, J=6.5 Hz, 6H), 1.54 (d, J=6.0 Hz, 12H), 3.94 (s, 3H), 5.55(m, 1H), 5.68 (m, 3H), 7.00 (d, J=7.5 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H),7.79 (d, J=8.0 Hz, 1H), 7.94(d, J=8.0 Hz, 2H), 8.92 (d, J=8.0 Hz, 1H),9.03 (dd, J1=8.0 Hz, J2=8.0 Hz 2H), 10.24 (s, 1H), 10.27 (s, 1H), 10.28(s, 1H); 13C NMR (125 MHz, CDCl3) d 22.17, 22.17, 22.20, 22.20, 52.35,68.56, 69.23, 69.33, 69.36, 117.32, 117.42, 117.86, 119.03, 120.02,125.03, 125.83, 126.12, 126.63, 126.81, 127.25, 134.52, 135.33, 137.88,138.71, 139.22, 149.67, 150.81, 150.87, 151.93, 162.78, 162.80, 163.46,165.47; HRMS (FAB) Submitted.

[0354] Biological Data

[0355] The helix mimetic molecules described in this application showchemical and biological properties that are analogous to those ofnatural a-helix peptides. Three biological targets were assessed forinhibition properties against different classes of-helix mimics.

[0356] Calmodulin and its Phosphodiesterase Activativating Properties.

[0357] To test the idea of a-helix mimicry by terphenyl derivatives, wefocussed on the interaction between calmodulin (CaM) and an α-helicaldomain of smooth muscle myosin light chain kinase (smMLCK).¹⁶ CaM alsorepresents an interesting target in our continuing search¹⁷ formolecules that influence cell cycle events.¹⁸ Moreover, earlier workfrom DeGrado has shown that CaM provides an effective recognitionsurface for a variety of peptides in an α-helical conformation.¹⁹ Thesequence of a 20-mer fragment (RS20) in smMLCK is shown in FIG. 12 andmutational studies have established a key role for three i,i+3 and i+7residues (Trp800, Thr803, and Val807) in binding to the C-terminaldomain of CaM in a complex that also involves the collapsed N-terminalregion.²⁰ The hydrophobic side chains of this key trio of residues canbe mimicked by the corresponding 3, 2′,2″-terphenyl a which, in astaggered conformation, should project them with a similar rise andangle to that in smMLCK. For synthetic simplicity we changed the indoleof Trp800 to phenyl and removed the hydroxyl of Thr803. Using Negishicouplings of differently substituted phenyltriflates, we preparedterphenyl a as a mimic of the calmodulin binding face of smMLCK. Thefree hydroxyl at the end of the iterative terphenyl synthesis wasalkylated with benzyl bromoacetate, the ester was hydrolyzed and theresulting carboxylic acid was converted to the ammonium salt of a, whichproved to be surprisingly soluble in buffer with <1% DMSO. FIG. 12 showsa number of the derivatives synthesized and utilized in this assay.

[0358] Passage of a through an avidin based affinity resin derivatizedwith biotinylated CaM led to retention of the terphenyl on the column.Discrete complex formation to CaM was indicated by the release of a fromthe column, as monitored by HPLC, on elution with 5M biotin. The controlexperiment with an underivatized avidin resin resulted in no observableretention of a. In addition, polyacrylamide gel permeationchromatography (6 kD cutoff) showed that 2 alone (70 μM in buffer) wasretained on the column but passed through when mixed with one equivalentof CaM, due presumably to the formation of a CaM:a complex. To amplifythe binding event between CaM and a, an enzymatic assay was alsoemployed. CaM activates the enzyme 3′-5′ cyclic nucleotidephosphodiesterase (PDE) through an interaction that is thought toinvolve the same hydrophobic region that binds to smMLCK.²¹ Addition ofa to a solution of CaM and PDE caused a dose-dependant reduction in theability of CaM to activate the enzyme for the hydrolysis of substrate(FIG. 13).²² The inhibitory potency of a (IC₅₀=800 nM) in this PDE assayis only 10-fold less than the 20-mer α-helical peptide RS20 (IC₅₀=80 nM)and much stronger than the trimethylterphenyl d (IC₅₀>20 μM)²³ thatlacks the trio of binding substituents or monophenyl e (IC₅₀=150 μM).This result suggests that a acts as a functional mimic of a natural CaMsubstrate by antagonizing the binding interaction between CaM and PDE.FIG. 13 shows the antagonism of CaM by monitoring PDE hydrolysis ofsubstrate in the presence of inhibitors.

[0359] 1- and 2-naphthyl derivatives b and c as improved analogs of theTrp800 indole side chain in smMLCK. FIG. 13 shows that both b and c arevery potent inhibitors of CaM activation of PDE enzyme activity withIC₅₀ values of 9 nM and 20 nM, respectively. For b this potencycorresponds to an 8-fold improvement over the helical peptide RS20 fromsmMLCK and renders it among the most active CaM antagonists known.However, the full extent of helix mimicry by a, b, and c in terms oftheir precise conformations and modes of binding to CaM awaitshigh-resolution structures of these complexes.

[0360] gp41-Virus Fusion Protein

[0361] We have designed a proteomimetic of an α-helical 4-3 hydrophobicrepeat that inhibits the assembly of a six helix bundle corresponding tothe fusion-active conformnation of gp41 protein.²⁴ This intra-proteinsurface disruption results in reduced levels of HIV-1 entry into hostcells. The gp41 ectodomain contains a N-terminal glycine-rich fusionsequence, as well as two helical regions containing hydrophobic 4-3heptad (abcdefg) repeats denoted as the N and C helical regions. Recentevidence has shown that upon binding target surface cell receptors gp41undergoes a conformational change which exposes the hydrophobic N helixregions and allows the fusion peptides to insert into the host cellmembrane. This transient gp41 intermediate then re-folds into astabilized six helix bundle structure, which brings both the viral andtarget cell membranes into proximity resulting in completion of thefusion process. The fusion-critical helix bundle has been shown by X-raydiffraction data to exist as a gp41 trimer in which the N helix regionsform a parallel trimeric coiled-coil and the C helix regionssubsequently pack in an antiparallel fashion into the hydrophobicgrooves formed by the coiled-coil.

[0362] Antagonists that bind the exposed N helix regions of thetransient gp41 intermediate can potentially trap this structure prior tobundle formation, leading to inhibition of viral fusion.²⁵ Peptides withsequences corresponding to the C helix region of gp41 are potentinhibitors of HIV fusion, one of which is currently in human trials.²⁶Small molecules that bind into a hydrophobic pocket in the N helixtrimer inhibit viral fusion in vitro, with activities in the lowmicromolar range.²⁷ However, other sites along the hydrophobic groovesof the N helix trimer are also important for C helix recognition,²⁸ asevidenced by the strong binding of C-terminal peptides that lack the keyTrp residues (W₆₂₈ and W₆₃₁ in gp41). Also, small peptides correspondingto the pocket binding region have negligible viral fusion inhibition andmutations of C peptide residues distant from the W₆₂₈ and W₆₃₁ bindingregion abolish inhibition activity.²⁹

[0363] Tris-functionalized 3,2′,2″-terphenyl derivatives serve aseffective mimics of the surface functionality projected along one faceof an α-helix. To target the gp41 complex we prepared terphenylderivative f, which mimics the side chains of a i,i+4, i+7 dadhydrophobic surface as found in the C and N heptad repeat regions.Although there are a range of hydrophobic residues at the a and dpositions, Leu and Ile are the most prevalent. Therefore, we haveincorporated related branched alkyl substituents, isobutyl and isopropyl(to avoid complications from chirality in sec-butyl group), into ourinitial design. Terminal carboxylate groups were also added to mimic theanionic character of the C peptide helix and to improve the aqueoussolubility. A number of these compounds are presented in attached FIG.14. The ability of f to influence the disruption of the gp41 core wasstudied using CD spectroscopy. A model system composed of two peptides(N36 and C34), from the N and C heptad repeat regions of gp41, forms astable six helix bundle (T_(m)=66° C.) that is analogous to the gp41core. CD experiments show that the C34 peptide alone in solution israndom coil and the N36 peptide forms concentration dependentaggregates. Titration of f into a 10 μM solution (50 mM PBS, 150 mMNaCl, pH 7.0, 4° C.) of the preformed gp41 core model resulted in adecrease of the CD signal at Θ222 and 208 nm, corresponding to areduction in the helicity of the hexameric bundle. A plot of Θ222 versusinhibitor concentration (FIG. 15) shows saturation at approximatelythree equivalents of f. The CD spectrum with excess f was similar to thetheoretical addition of the individual N36 and C34 spectra at the sameconcentration. Both the hydrophobic and electrostatic features of f areimportant for its ability to disrupt the bundle. Analogs h and i,lacking the key alkyl side chains and analog g with positively chargedsubstituents on the hydrophobic core have little effect on the proteinCD spectrum even at high concentrations (FIG. 16). To test the scope ofthis strategy we have increased the size of the hydrophobic substituentsin f, using the bis-benzyl substituted j. This molecule shows a modestenhancement in activity compared to f (FIG. 16), fully disrupting thehexameric bundle at a lower concentration. The disruption of thehexameric bundle seen in the CD experiments was supported by an ELISAfor gp41 core disruption using an antibody that binds the N36/C34 helixbundle but not the individual peptides. Mimetic f effectively disruptsN36/C34 complexation with an IC₅₀ of 13.18±2.54 μg/ml in comparison tog-i which have no effect at 100 μg/ml.

[0364] Finally, the effects of antagonist f on HIV-1 mediated fusionwere studied using a dye transfer cell fusion assay.³⁰ If the gp41 coreis being disrupted, as implied by the CD and ELISA experiments, then thefusion mechanism of HIV-1 should be inhibited. Indeed, f showsinhibition of HIV-1 mediated cell-to-cell fusion with an IC₅₀ of15.70±1.30 μg/. In comparison, compounds g-i had no inhibitory activityand proved to be cytotoxic at similar concentrations.

[0365] BcLxL/Bak Complex in Apoptosis

[0366] To further extend this strategy we tried to mimic parts of theα-helical, pro-apoptotic Bak- and Bad-proteins, which interact byheterodimerization with the anti-apoptotic protein BCl-x_(L). BCl-x_(L)is overexpressed in many types of cancer and protects transformed cellsfrom cell death, leading to uncontrolled cell growth even if apoptoticsignals generated by chemo- or radiotherapy are present. A designedBak/Bad-mimetic could interact with the anti-apoptotic Bcl-x_(L) proteinand thus enable the apoptotic cascade leading to cell death. We basedour design on the crystal and solution structures of BCl-x_(L), whichshow the helical Bak-peptide binding into a hydrophobic cleft formed bythe BH1-BH3 domains of Bcl-x_(L). From alanine scans of the Bak-peptideit is clear that four hydrophobic residues (Val⁷⁴, Leu⁷⁸, Ile⁸¹, Ile⁸⁵)along one edge of the helix are involved in binding. In addition, Asp⁸³forms an ion pair with a lysine residue of BCl-x_(L). A related 26-merpeptide derived from the Bad-protein binds better to Bcl-x_(L),exploiting larger hydrophobic residues (Tyr, Phe) to induce a slightstructural change in the binding region of BCl-x_(L).

[0367] Based on these structural requirements we designed a series ofterphenyl molecules (k-n) containing alkyl or aryl substituents on thethree ortho positions (to mimic the key i, i+3, and i+7 groups in Bak orBad) and carboxylic acid substituents on either end (to mimic theadditional ion pair) (FIG. 17). The binding affinity of these moleculesfor BCl-x_(L) was assessed by a fluorescence polarization assay usingfluoresceine-labeled 16-mer Bak-peptide. Displacement of this probethrough competitive binding of the terphenyl into the hydrophobic cleftof BCl-x_(L) would lead to a decrease in its fluorescence polarizationwhich in turn could be related to the known affinity of the 16-merBak/Bcl-x_(L) complex. This assay showed (FIG. 18) that the terphenylmolecule with two carboxylic acids and the isobutyl,1-naphthalenemethylene, isobutyl sequence (m) shows the strongestbinding to BCl-x_(L) with a K_(D)-value of 114 nM, whereas lesshydrophobic terphenyls with only alkyl side chains (k) or with onebenzyl side chain (l) show less binding affinity, emphasizing theimportance of hydrophobic interactions for binding to the hydrophobiccleft in BCl-x_(L). The analogue compound n with thenaphthalenemethylene side chain at the top phenyl unit shows asignificant loss in binding affinity indicating the importance of therelative positions of the terphenyl side chains.

[0368] It is to be understood by those skilled in the art that theforegoing description and examples are illustrative of practicing thepresent invention, but are in no way limiting. Variations of the detailpresented herein may be made without departing from the spirit and scopeof the present invention as defined by the following claims.

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[0394] 26 a) R. A. Furuta, C. T. Wild, Y. Weng, C. D. Weiss, Nat.Struct. Biol. 1998, 5, 276-279; B)J. M. Kilby, S. Hopkins, T. M.Venetta, B. DiMassimo, G. A. Cloud, J. Y. Lee, L. Alldredge, E. Hunter,D. Lambert, D. Bolognesi, T. Matthews, M. R. Johnson, M. A. Nowak, G. M.Shaw, M. S. Saag, Nat. Med. 1998, 4, 1302-1307.

[0395] 27. S. Jiang, K. Lin, N. Strick, A. R. Neurath, Biochem. Biophys.Res. Commun., 1993, 195, 533-538.

[0396] 28 For the role of the Bcl-2 protein family in apoptosis seee.g.: (a) A. Gross, J. M. McDonnell, S. J. Korsmeyer, Genes &Development 1999, 13, 1899-1911. (b) D. T. Chao, S. J. Korsmeyer, Annu.Rev. Immunol. 1998, 16, 395-419

[0397] 29 structure reviews: (a) S. W. Fesik, Cell 2000, 103, 273-282.(b) H. Liang, S. W. Fesik, J. Mol. Biol. 1997, 274, 291-302.

[0398] 30 M. Sattler, H. Liang, D. Nettesheim, R. P. Meadows, J. E.Harlan, M. Eberstadt, H. S. Yoon, S. B. Shuker, B. S. Chang, A. J. Minn,C. B. Thompson, S. W. Fesik, Science 1997, 275, 983-986.

We claim:
 1. A compound or its pharmaceutically acceptable salt of theformula: W—B—X—B—YWhere X is selected from the group consisting of afive or six-membered ring selected from the group consisting of:

 or a fused-ring system selected from the group consisting of W and Yare each independently selected from the group consisting of

Where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each independentlyselected from the group consisting of unsubstituted or substitutedhydrocarbon groups, unsubstituted or substituted aryl, unsubstituted orsubstituted alkylene aryl, unsubstituted or substituted alkylaryl,alkoxy, ester, alkanol, alkanoic acid, thioether, thioester, amine,alkylamine, dialkylamine, unsubstituted or substituted amide oralkyleneamide, unsubstituted or substituted alkyleneamine, unsubstitutedor substituted alkyleneguanidine; R_(n) is a C₁-C₁₀ alkyl, alkanol, arylor a

 group, where T is H or a C₁-C₁₂ saturated or unsaturated hydrocarbon,amine, alkylamine, dialkylamine, unsubstituted or substitutedalkyleneamine or unsubstituted or substituted alkyleneamide; Z is O orS; B is a single bond between carbon atoms of W—X or X—Y groups or anester or amide group linking W—X or X—Y groups.
 2. The compoundaccording to claim 1 wherein X is selected from the group consisting of

W and Y are selected from the group consisting of

and B is a single bond between carbon atoms of W—X or X—Y groups or anamide group linking W—X or X—Y groups.
 3. The compound according toclaim 2 wherein X is selected from the group consisting of


4. The compound according to claim 1 wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸ and R⁹ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, benzyl, phenyl, naphthyl, 4-hydroxybenzyl, C₁-C₆alkanol, C₁-C₆ alkanoic acid, C₁-C₆ alkylamide, C₁-C₆ alkyleneamine,C₁-C₆ alkyleneguanidine with the proviso that no more than two Rsubstituents on each of W, X or Y groups are other than H; R_(n) is aC₁-C₁₀ alkyl, alkanol, aryl or a

 group, where T is H or a C₁-C₆ alkyl, amine, C₁-C₆ alkylamine, C₁-C₆dialkylamine, unsubstituted or substituted C₁-C₆ alkyleneamine orunsubstituted or substituted C₁-C₆ alkyleneamide; Z is O or S; and B isa single bond between carbon atoms of W—X or X—Y groups or an amidegroup linking W—X or X—Y groups.
 5. The compound according to claim 4wherein W, X and Y are selected from the group consisting of

and B is a single bond between carbon atoms of W—X or X—Y groups or anamide group linking W—X or X—Y groups.
 6. The compound according toclaim 1 wherein W, X and Y are each

and B is a single bond between carbon atoms of W—X or X—Y groups or anamide group linking W—X or X—Y groups.
 7. The compound according toclaim 1 wherein W, X and Y are each

and B is a single bond between carbon atoms of W—X or X—Y groups or anamide group linking W—X or X—Y groups.
 8. The compound according toclaim 1 wherein W, X and Y are each

and B is a single bond between carbon atoms of W—X or X—Y groups or anamide group linking W—X or X—Y groups.
 9. The compound according toclaim 6 wherein R¹, R², R³, and R⁴ are each independently selected fromthe group consisting of are each independently selected from the groupconsisting of H, C₁-C₆ alkyl, benzyl, phenyl, naphthyl, 4-hydroxybenzyl,C₁-C₆ alkanol, C₁-C₆ alkyl alkylene thioether, C₁-C₆ alkanoic acid,C₁-C₆ alkylamide, C₁-C₆ alkyleneamine and C₁-C₆ alkyleneguanidine, withthe proviso that no more than two R substituents on each of W, X or Ygroups are other than H; and B is a single bond between carbon atoms ofW—X or X—Y groups or an amide group linking W—X or X—Y groups.
 10. Thecompound according to claim 7 wherein R¹, R², R³, and R⁴ are eachindependently selected from the group consisting of are eachindependently selected from the group consisting of H, C₁-C₆ alkyl,benzyl, phenyl, naphthyl, 4-hydroxybenzyl, C₁-C₆ alkanol, C₁-C₆ alkylalkylene thioether, C₁-C₆ alkanoic acid, C₁-C₆ alkylamide, C₁-C₆alkyleneamine and C₁-C₆ alkyleneguanidine, with the proviso that no morethan two R substituents on each of W, X or Y groups are other than H;and B is a single bond between carbon atoms of W—X or X—Y groups or anamide group linking W—X or X—Y groups.
 11. The compound according toclaim 8 wherein R¹, R², and R³ are each independently selected from thegroup consisting of are each independently selected from the groupconsisting of H, C₁-C₆ alkyl, benzyl, phenyl, naphthyl, 4-hydroxybenzyl,C₁-C₆ alkanol, C₁-C₆ alkyl alkylene thioether, C₁-C₆ alkanoic acid,C₁-C₆ alkylamide, C₁-C₆ alkyleneamine and C₁-C₆ alkyleneguanidine, withthe proviso that no more than two R substituents on each of W, X or Ygroups are other than H; and B is a single bond between carbon atoms ofW—X or X—Y groups or an amide group linking W—X or X—Y groups.
 12. Apharmaceutical composition comprising an effective amount of a compoundof the formula: W—B—X—B—YWhere X is selected from the group consistingof a five or six-membered ring selected from the group consisting of:

 or a fused-ring system selected from the group consisting of

W and Y are each independently selected from the group consisting of

Where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each independentlyselected from the group consisting of unsubstituted or substitutedhydrocarbon groups, unsubstituted or substituted aryl, unsubstituted orsubstituted alkylene aryl, unsubstituted or substituted alkylaryl,alkoxy, ester, alkanol, alkanoic acid, thioether, thioester, amine,alkylamine, dialkylamine, unsubstituted or substituted amide oralkyleneamide, unsubstituted or substituted alkyleneamine, unsubstitutedor substituted alkyleneguanidine; R_(n) is a C₁-C₁₀ alkyl, alkanol, arylor a

 group, where T is H or a C₁-C₁₂ saturated or unsaturated hydrocarbon,amine, alkylamine, dialkylamine, unsubstituted or substitutedalkyleneamine or unsubstituted or substituted alkyleneamide; Z is O orS; and B is a single bond between carbon atoms of W—X or X—Y groups oran ester or amide group linking W—X or X—Y groups; or itspharmaceutically acceptable salt, optionally, in combination with apharmaceutically acceptable carrier, additive or excipient.
 13. Thecompound according to claim 12 wherein X is selected from the groupconsisting of

W and Y are selected from the group consisting of

and B is a single bond between carbon atoms of W—X or X—Y groups or anamide group linking W—X or X—Y groups.
 14. The compound according toclaim 13 wherein X is selected from the group consisting of


15. The compound according to claim 12 wherein R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸ and R⁹ are each independently selected from the group consistingof H, C₁-C₆ alkyl, benzyl, phenyl, naphthyl, 4-hydroxybenzyl, C₁-C₆alkanol, C₁-C₆ alkanoic acid, C₁-C₆ alkylamide, C₁-C₆ alkyleneamine,C₁-C₆ alkyleneguanidine with the proviso that no more than two Rsubstituents on each of W, X or Y groups are other than H; R_(n) is aC₁-C₁₀ alkyl, alkanol, aryl or a

 group, where T is H or a C₁-C₆ alkyl, amine, C₁-C₆ alkylamine, C₁-C₆dialkylamine, unsubstituted or substituted C₁-C₆ alkyleneamine orunsubstituted or substituted C₁-C₆ alkyleneamide; Z is O or S; and B isa single bond between carbon atoms of W—X or X—Y groups or an amidegroup linking W—X or X—Y groups.
 16. The compound according to claim 15wherein W, X and Y are selected from the group consisting of

and B is a single bond between carbon atoms of W—X or X—Y groups or anamide group linking W—X or X—Y groups.
 17. The compound according toclaim 12 wherein W, X and Y are each

and B is a single bond between carbon atoms of W—X or X—Y groups or anamide group linking W—X or X—Y groups.
 18. The compound according toclaim 12 wherein W, X and Y are each

and B is a single bond between carbon atoms of W—X or X—Y groups or anamide group linking W—X or X—Y groups.
 19. The compound according toclaim 12 wherein W, X and Y are each

and B is a single bond between carbon atoms of W—X or X—Y groups or anamide group linking W—X or X—Y groups.
 20. The compound according toclaim 17 wherein R¹, R², R³, and R⁴ are each independently selected fromthe group consisting of are each independently selected from the groupconsisting of H, C₁-C₆ alkyl, benzyl, phenyl, naphthyl, 4-hydroxybenzyl,C₁-C₆ alkanol, C₁-C₆ alkyl alkylene thioether, C₁-C₆ alkanoic acid,C₁-C₆ alkylamide, C₁-C₆ alkyleneamine and C₁-C₆ alkyleneguanidine, withthe proviso that no more than two R substituents on each of W, X or Ygroups are other than H; and B is a single bond between carbon atoms ofW—X or X—Y groups or an amide group linking W—X or X—Y groups.
 21. Thecompound according to claim 18 wherein R¹, R², R³, and R⁴ are eachindependently selected from the group consisting of are eachindependently selected from the group consisting of H, C₁-C₆ alkyl,benzyl, phenyl, naphthyl, 4-hydroxybenzyl, C₁-C₆ alkanol, C₁-C₆ alkylalkylene thioether, C₁-C₆ alkanoic acid, C₁-C₆ alkylamide, C₁-C₆alkyleneamine and C₁-C₆ alkyleneguanidine, with the proviso that no morethan two R substituents on each of W, X or Y groups are other than H;and B is a single bond between carbon atoms of W—X or X—Y groups or anamide group linking W—X or X—Y groups.
 22. The compound according toclaim 19 wherein R¹, R², and R³ are each independently selected from thegroup consisting of are each independently selected from the groupconsisting of H, C₁-C₆ alkyl, benzyl, phenyl, naphthyl, 4-hydroxybenzyl,C₁-C₆ alkanol, C₁-C₆ alkyl alkylene thioether, C₁-C₆ alkanoic acid,C₁-C₆ alkylamide, C₁-C₆ alkyleneamine and C₁-C₆ alkyleneguanidine, withthe proviso that no more than two R substituents on each of W, X or Ygroups are other than H; and B is a single bond between carbon atoms ofW—X or X—Y groups or an amide group linking W—X or X—Y groups.
 23. Amethod of treating, preventing or reducing the likelihood of a conditionor disease state in a patient, said condition or disease state beingmodulated through the interaction of an α-helical protein with a bindingsite of said protein, said method comprising administering to a patientin need of therapy an effective amount of one or more compoundsaccording to claim 1, optionally in a pharmaceutically acceptablecarrier, additive or excipient.
 24. The method according to claim 23wherein said condition or disease state is selected from the groupconsisting of viral infections, (including Hepatitis B virus (HBV)infections, human immunodeficiency virus (HIV) infections or conditionsassociated with such infections (AIDS), Herpes Simplex virus infections(HSV) infections, tumors and/or cancer, proliferative diseases includingpsoriasis, genital warts and hyperproliferative keratinocyte diseaseincluding hyperkeratosis, ichthyosis, keratoderma, lichen planus,hypertension, neuronal disorders, asthma, autoimmune diseases includinglupus (lupus erythematosus), multiple sclerosis, arthritis, includingrheumatoid arthritis, rheumatic diseases, fibromyalgia, Sjögren'sdisease and Grave's disease and neurodegenerative diseases includingAlzheimer's disease and Parkinson's disease.
 25. The method according toclaim 24 wherein said viral infection is a Hepatitis B virus (HBV)infection, a human immunodeficiency virus (HIV) or a Herpes Simplexvirus (HSV) infection.
 26. The method according to claim 24 wherein saidhyperproliferative keratinocyte disease is selected from the groupconsisting of hyperkeratosis, ichthyosis, keratoderma and lichen planus.27. The method according to claim 24 wherein said autoimmune disease isselected from the group consisting of lupus erythematosus, multiplesclerosis, arthritis, rheumatic diseases, fibromyalgia, Sjögren'sdisease and Grave's disease.
 28. The method according to claim 24wherein said neurodegenerative disease is selected from the groupconsisting of Alzheimer's disease and Parkinson's disease.
 29. Themethod according to claim 24 wherein said disease or condition isselected from the group consisting of attention deficit disorder, memoryloss, language disorder and learning disorder.
 30. A method ofinhibiting a calmodulin dependent phosphodiesterase enzyme in a patient,said method comprising administering said patient and effective amountof a compound according to claim 1, optionally in combination with apharmaceutically acceptable additive, carrier or excipient.
 31. A methodof inhibiting Bcl-X_(L) in a patient, said method comprisingadministering to said patient an effective amount of a compoundaccording to claim 1 to said patient.
 32. A method of inhibitingcellular invasion of a virus in a patient, said method comprisingadministering to said patient an effective amount of a compoundaccording to claim 1 to said patient.
 33. The method according to claim32 wherein said virus is selected from the group consisting of HIV, HSVand HBV.
 34. A method of identifying a compound to be used as apeptideomimetic agent as an agonist or antagonist of an α-helicalprotein for its binding site, said method comprising providing acylindrical cage or rigid scaffold compound according to the structure:W—B—X—B—YWherein X is selected from the group consisting of a five orsix-membered ring selected from the group consisting of:

 or a fused ring system selected according to the structure:

W and Y are each independently selected from the group consisting of

and each B is indendently a connecting bond or an amide or ester groupconnecting W to said X and Y groups; said method further comprisingidentifying chemical groups that are sterically and electronicallysimilar to the substituents on the α carbon atoms of natural amino acidsand attaching said substituents to unbound atoms on the ring structuresof said chemical scaffold, said substituents providing similar stericand electrochemical characteristics to substitutents at the position ofthe α carbon atoms of a peptide or protein sequence in an α helicalprotein.
 35. The method according to claim 34 wherein said substituentis selected from the group consisting of hydrogen, C₁-C₆ alkanol,thioether, mercaptan, benzyl, hydroxybenzyl, C₁-C₆ alkyleneamide,ethyleneamide, C₁-C₆ alkanoic acid, C₁-C₆alkyleneamine,alkylene-1,3-pyrazole, C₁-C₆alkyleneguanidine and C₁-C₆ alkanolamine.36. The method according to claim 12 wherein said substituent isselected from the group consisting of hydrogen, methyl, isopropyl,isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, pyrrolidinyl, indole,methylmethylenethioether, methanol, 1-ethanol, acetate, propionate,methyleneamide, ethyleneamide, butyleneamine, propyleneguanidine,methylenepyrazole (histidinyl) and methylmercaptan.